Benzo-1,4-diazepin-2-ones as inhibitors of Aβ protein production

ABSTRACT

This invention relates to novel compounds of the class of succinoyl lactams, such as diazepinee of Formula (Id), 
                 
 
or a pharmaceutically acceptable salt thereof, as described above, having drug and bio-affecting properties. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of Alzheimer&#39;s disease.

CROSS-REFERENCE

This application is division of application Ser. No. 09/506,360, filedon Feb. 17, 2000 now U.S. Pat. No. 6,794,381, which is acontinuation-in-part of application Ser. No. 09/370,089, filed on Aug.6, 1999, now abandoned; claiming benefit of Provisional application No.60/120,227, filed on Feb. 15, 1999, abondoned; Provisional applicationNo. 60/113,558, filed on Dec. 3, 1998, abandoned; and Provisionalapplication No. 60/095,698, filed on Aug. 7, 1998, abandoned; all thedisclosures of which are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

This invention relates to novel lactams having drug and bio-affectingproperties, their pharmaceutical compositions and methods of use. Thesenovel compounds inhibit the processing of amyloid precursor protein and,more specifically, inhibit the production of Aβ-peptide, thereby actingto prevent the formation of neurological deposits of amyloid protein.More particularly, the present invention relates to the treatment ofneurological disorders related to β-amyloid production such asAlzheimer's disease and Down's Syndrome.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) is a degenerative brain disorder characterizedclinically by progressive loss of memory, temporal and localorientation, cognition, reasoning, judgment and emotional stability. ADis a common cause of progressive dementia in humans and is one of themajor causes of death in the United States. AD has been observed in allraces and ethnic groups worldwide, and is a major present and futurehealth problem. No treatment that effectively prevents AD or reversesthe clinical symptoms and underlying pathophysiology is currentlyavailable (for review, Dennis J. Selkoe; Cell Biology of the amyloid(beta)-protein precursor and the mechanism of Alzheimer's disease, AnnuRev Cell Biol, 1994, 10: 373-403).

Histopathological examination of brain tissue derived upon autopsy orfrom neurosurgical specimens in effected individuals revealed theoccurrence of amyloid plaques and neurofibrillar tangles in the cerebralcortex of such patients. Similar alterations were observed in patientswith Trisomy 21 (Down's syndrome), and hereditary cerebral hemorrhagewith amyloidosis of the Dutch-type. Neurofibrillar tangles arenonmembrane-bound bundles of abnormal proteinaceous filaments andbiochemical and immunochemical studies led to the conclusion that theirprinciple protein subunit is an altered phosphorylated form of the tauprotein (reviewed in Selkoe, 1994).

Biochemical and immunological studies revealed that the dominantproteinaceous component of the amyloid plaque is an approximately 4.2kilodalton (kD) protein of about 39 to 43 amino acids. This protein wasdesignated Aβ, β-amyloid peptide, and sometimes β/A4; referred to hereinas Aβ. In addition to deposition of Aβ in amyloid plaques, Aβ is alsofound in the walls of meningeal and parenchymal arterioles, smallarteries, capillaries, and sometimes, venules. Aβ was first purified,and a partial amino acid reported, in 1984 (Glenner and Wong, Biochem.Biophys. Res. Commun. 120: 885-890). The isolation and sequence data forthe first 28 amino acids are described in U.S. Pat. No 4,666,829.

Compelling evidence accumulated during the last decade revealed that Aβis an internal polypeptide derived from a type 1 integral membraneprotein, termed β amyloid precursor protein (APP). β APP is normallyproduced by many cells both in vivo and in cultured cells, derived fromvarious animals and humans. Aβ is derived from cleavage of β APP by asyet unknown enzyme (protease) system(s), collectively termed secretases.

The existence of at least four proteolytic activities has beenpostulated. They include β secretase(s), generating the N-terminus ofAβ, a secretase(s) cleaving around the 16/17 peptide bond in Aβ, and γsecretases, generating C-terminal Aβ fragments ending at position 38,39, 40, 42, and 43 or generating C-terminal extended precursors whichare subsequently truncated to the above polypeptides.

Several lines of evidence suggest that abnormal accumulation of Aβ playsa key role in the pathogenesis of AD. Firstly, Aβ is the major proteinfound in amyloid plaques. Secondly, Aβ is neurotoxic and may be causallyrelated to neuronal death observed in AD patients. Thirdly, missense DNAmutations at position 717 in the 770 isoform of β APP can be found ineffected members but not unaffected members of several families with agenetically determined (familiar) form of AD. In addition, several otherβ APP mutations have been described in familiar forms of AD. Fourthly,similar neuropathological changes have been observed in transgenicanimals overexpressing mutant forms of human b APP. Fifthly, individualswith Down's syndrome have an increased gene dosage of β APP and developearly-onset AD. Taken together, these observations strongly suggest thatAβ depositions may be causally related to the AD.

It is hypothesized that inhibiting the production of Aβ will prevent andreduce neurological degeneration, by controlling the formation ofamyloid plaques, reducing neurotoxicity and, generally, mediating thepathology associated with Aβ production. One method of treatment methodswould therefore be based on drugs that inhibit the formation of Aβ invivo.

Methods of treatment could target the formation of Aβ through theenzymes involved in the proteolytic processing of b amyloid precursorprotein. Compounds that inhibit b or g secretase activity, eitherdirectly or indirectly, could control the production of Aβ.Advantageously, compounds that specifically target g secretases, couldcontrol the production of Aβ. Such inhibition of β or γ secretases couldthereby reduce production of Aβ, which, thereby, could reduce or preventthe neurological disorders associated with Aβ protein.

PCT publication number WO 96/29313 discloses the general formula:

covering metalloprotease inhibiting compounds useful for the treatmentof diseases associated with excess and/or unwanted matrixmetalloprotease activity, particularly collagenase and or stromelysinactivity.

Compounds of general formula:

are disclosed in PCT publication number WO 95/22966 relating to matrixmetalloprotease inhibitors. The compounds of the invention are usefulfor the treatment of conditions associated with the destruction ofcartilage, including corneal ulceration, osteoporosis, periodontitis andcancer.

European Patent Application number EP 0652009A1 relates to the generalformula:

and discloses compounds that are protease inhibitors that inhibit Aβproduction.

U.S. Pat. No. 5,703,129 discloses the general formula:

which covers 5-amino-6-cyclohexyl-4-hydroxy-hexanamide derivatives thatinhibit Aβ production and are useful in the treatment of Alzheimer'sdisease.

None of the above references teaches or suggests the compounds of thepresent invention which are described in detail below.

SUMMARY OF THE INVENTION

One object of the present invention is to provide novel compounds whichare useful as inhibitors of the production of Aβ protein orpharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

It is another object of the present invention to provide a method fortreating degenerative neurological disorders comprising administering toa host in need of such treatment a therapeutically effective amount ofat least one of the compounds of the present invention or apharmaceutically acceptable salt or prodrug form thereof.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of Formula (I):

or pharmaceutically acceptable salt or prodrug forms thereof, whereinR³, R^(3a), R⁵, R^(5a), R⁶, A, Q, B, W, X, Y, and Z are defined below,are effective inhibitors of the production of Aβ.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Thus, in a first embodiment, the present invention provides a novelcompound of Formula (I):

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein:-   A is O or S;-   Q is —OR¹ or —NR¹R²;-   R¹, at each occurrence, is independently selected from:    -   H;    -   C₁-C₆ alkyl substituted with 0-3 R^(1a);    -   C₂-C₆ alkenyl substituted with 0-3 R^(1a);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);    -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); and    -   5 to 10 membered heterocycle substituted with 0-3 R^(1b);-   R^(1a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);    -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); and    -   5 to 6 membered heterocycle substituted with 0-3 R^(1b);-   R^(1b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,    C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy;-   R² is independently selected from H, NH₂, OH, C₁-C₆ alkyl, C₁-C₆    alkoxy, phenoxy, benzyloxy, C₃-C₁₀ carbocycle, C₆-C₁₀ aryl and 5 to    10 membered heterocycle;-   R³ is —(CR⁷R^(7a))_(n)—R⁴,    -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—S(═O)—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—S(═O)₂—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—C(═O)—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—N(R^(7b))C(═O)—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—C(═O)N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—N(R^(7b))S(═O)₂—(CR⁷R^(7a))_(m)—R⁴, or    -   —(CR⁷R^(7a))_(n)—S(═O)₂N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴;-   n is 0, 1, 2, or 3;-   m is 0, 1, 2, or 3;-   R^(3a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₂-C₄ alkenyloxy;-   R⁴ is H, OH, OR^(14a),    -   C₁-C₆ alkyl substituted with 0-3 R^(4a),    -   C₂-C₆ alkenyl substituted with 0-3 R^(4a),    -   C₂-C₆ alkynyl substituted with 0-3 R^(4a),    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from is H, F,    Cl, Br, I, CF₃,    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ halothioalkoxy;-   R⁵ is H, OR¹⁴;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₁-C₆ alkoxy substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle substituted with 0-3R^(5c);-   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄    alkenyloxy;-   R^(5b), at each occurrence, is independently selected from:    -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ halothioalkoxy;-   R⁶ is H;    -   C₁-C₆ alkyl substituted with 0-3 R^(6a);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(6b); or    -   C₆-C₁₀ aryl substituted with 0-3R^(6b);-   R^(6a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, phenyl or CF₃;-   R^(6b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,    C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy;-   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,    Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl;-   R^(7a), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, CF₃, aryl and C₁-C₄ alkyl;-   R^(7b) is independently selected from H and C₁-C₄ alkyl;-   W is —(CR⁸R^(8a))_(p)—;-   p is 0, 1, 2, 3, or 4;-   R⁸ and R^(8a), at each occurrence, are independently selected from    H, F, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl and C₃-C₈    cycloalkyl;-   X is a bond;    -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(Xb); or    -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ halothioalkoxy;-   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—;-   t is 0, 1, 2, or 3;-   u is 0, 1, 2, or 3;-   R⁹ and R^(9a), at each occurrence, are independently selected from    H, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,    —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,    —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or    —OC(═O)—;-   Z is C₁-C₄ alkyl substituted with 0-3 R^(12b);    -   C₁-C₃ alkyl substituted with 1-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ halothioalkoxy;-   B is a 5 to 10 membered lactam or thiolactam,    -   wherein the lactam or thiolactam is saturated, partially        saturated or unsaturated;    -   wherein each additional lactam carbon or thiolactam carbon is        substituted with 0-2 R¹¹; and,    -   optionally, the lactam or thiolactam contains a heteroatom        selected from —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—;-   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,    S(═O)₂R¹⁷;    -   C₁-C₆ alkyl substituted with 0-2 R^(10a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or    -   5 to 10 membered heterocycle optionally substituted with 0-3        R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or aryl    substituted with 0-4 R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,    acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄    haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ halothioalkoxy;-   R¹¹, at each occurrence, is independently selected from    -   C₁-C₄ alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷,        C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;    -   C₁-C₆ alkyl substituted with 0-1 R^(11a);    -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(11b);-   alternatively, two R¹¹ substituents on the same or adjacent carbon    atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused    radical;-   R^(11a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl    substituted with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ halothioalkoxy;-   R¹⁴, at each occurrence, is independently selected from H, phenyl,    benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl;-   R^(14a) is H, phenyl, benzyl, or C₁-C₄ alkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl);-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl);-   R¹⁷ is H, aryl, aryl-CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl;-   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl); and-   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and    —S(═O)₂—(C₁-C₆ alkyl); and-   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or    phenethyl.

In a preferred embodiment the present provides

-   A is O;-   Q is —NR¹R²;-   R¹, at each occurrence, is independently selected from:    -   H;    -   C₁-C₆ alkyl substituted with 0-3 R^(1a);    -   C₂-C₆ alkenyl substituted with 0-3 R^(1a);-   R^(1a), at each occurrence, is independently selected from H, OR¹⁴,    F, ═O, NR¹⁵R¹⁶, CF₃;    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(1b);    -   phenyl substituted with 0-3 R^(1b); and

5 to 6 membered heterocycle substituted with 0-3 R^(1b);

-   R^(1b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy,    C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy;-   R² is independently selected from H, NH₂, OH, C₁-C₆ alkyl, C₁-C₆    alkoxy, phenoxy, and benzyloxy;-   R³ is —(CR⁷R^(7a))_(n)—R⁴,    -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—S(═O)—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—S(═O)₂—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—C(═O)—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—NHC (═O)—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a) )_(n)—C(═O)NH—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—NHS(═O)₂—(CR⁷R^(7a))_(m)—R⁴, or    -   —(CR⁷R^(7a))_(n)—S(═O)₂NH—(CR⁷R^(7a))_(m)—R⁴;-   n is 0, 1, 2, or 3;-   m is 0, 1, 2, or 3;-   R^(3a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₂-C₄ alkenyloxy;-   R⁴ is H, OH, OR^(14a),    -   C₁-C₆ alkyl substituted with 0-3 R^(4a),    -   C₂-C₆ alkenyl substituted with 0-3 R^(4a),    -   C₂-C₆ alkynyl substituted with 0-3 R^(4a),    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from is H, F,    Cl, Br, I, CF₃,    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   R⁵ is H, OR¹⁴;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₁-C₆ alkoxy substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle substituted with 0-3R^(5c);-   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄    alkenyloxy;-   R^(5b), at each occurrence, is independently selected from:    -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   R⁶ is H;    -   C₁-C₆ alkyl substituted with 0-3 R^(6a);    -   C₃-C₆ carbocycle substituted with 0-3 R^(6b); or    -   C₆-C₁₀ aryl substituted with 0-3R^(6b);-   R^(6a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, phenyl or CF₃;-   R^(6b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,    C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy;-   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,    Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl;-   R^(7a), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, CF₃, aryl and C₁-C₄ alkyl;-   R^(7b) is independently selected from H and C₁-C₄ alkyl;-   W is —(CR⁸R^(8a))_(p)—; p is 0, 1, 2, 3, or 4;-   R⁸ and R^(8a), at each occurrence, are independently selected from    H, F, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl and C₃-C₈    cycloalkyl;-   X is a bond;    -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(Xb); or    -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—;-   t is 0, 1, 2, or 3;-   u is 0, 1, 2, or 3;-   R⁹ and R^(9a), at each occurrence, are independently selected from    H, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,    C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—, —S(═O)₂NR^(19b)—,    —NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or —OC(═O)—;-   Z is C₁-C₃ alkyl substituted with 1-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   B is a 6, 7, or 8 membered lactam,    -   wherein the lactam is saturated, partially saturated or        unsaturated;    -   wherein each additional lactam carbon is substituted with 0-2        R¹¹; and,    -   optionally, the lactam contains a heteroatom selected from —O—,        —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—;-   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,    S(═O)₂R¹⁷;    -   C₁-C₆ alkyl substituted with 0-1 R^(10a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or    -   5 to 10 membered heterocycle optionally substituted with 0-3        R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl    substituted with 0-4 R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃;-   R¹¹, at each occurrence, is independently selected from    -   C₁-C₄ alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷,        C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;    -   C₁-C₆ alkyl substituted with 0-1 R^(11a);    -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(11b);-   alternatively, two R¹¹ substituents on the same or adjacent carbon    atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused    radical;-   R^(11a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl    substituted with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,    C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy;-   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl);-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl);-   R¹⁷ is H, aryl, (aryl)CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl;-   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl); and-   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and    —S(═O)₂—(C₁-C₆ alkyl); and-   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or    phenethyl.

In a further preferred embodiment the present invention provides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein:-   R³ is —(CR⁷R^(7a))_(n)—R⁴,    -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or    -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴;-   n is 0, 1, or 2;-   m is 0, 1, or 2;-   R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, or butoxy;-   R⁴ is H, OH, OR^(14a),    -   C₁-C₄ alkyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkynyl substituted with 0-2 R^(4a),    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from is    -   H, F, Cl, Br, I CF₃,    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   R⁵ is H, OR¹⁴;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle substituted with 0-3R^(5c);-   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄    alkenyloxy;-   R^(5b), at each occurrence, is independently selected from:    -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   R⁶ is H, methyl, or ethyl;-   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,    Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl;-   R^(7a), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, CF₃, phenyl and C₁-C₄ alkyl;-   R^(7b) is independently selected from H, methyl, ethyl, propyl, and    butyl;-   W is —(CR⁸R^(8a))_(p)—;-   p is 0, 1, or 2;-   R⁸ and R^(8a), at each occurrence, are independently selected from    H, F, C₁-C₃ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl and C₃-C₆    cycloalkyl;-   X is a bond;    -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);    -   C₃-C₁₀ carbocycle substituted with 0-2 R^(Xb); or    -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—;-   t is 0, 1, or 2;-   u is 0, 1, or 2;-   R⁹ and R^(9a), at each occurrence, are independently selected from    H, F, C₁-C₄ alkyl or C₃-C₆ cycloalkyl;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,    —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,    —S(═O)₂NR^(19b)—, NR^(19b)S(═O)—, or —S(═O)NR^(19b)—,-   Z is C₁-C₃ alkyl substituted with 1-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   B is a seven membered lactam,    -   wherein the lactam is saturated, partially saturated or        unsaturated;    -   wherein each additional lactam carbon is substituted with 0-2        R¹¹; and,    -   optionally, the lactam contains a heteroatom selected from —O—,        —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—;-   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,    S(═O)₂R¹⁷;    -   C₁-C₆ alkyl substituted with 0-1 R^(10a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or    -   5 to 10 membered heterocycle optionally substituted with 0-3        R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl    substituted with 0-4 R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃;-   R¹¹, at each occurrence, is independently selected from    -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷,        C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;    -   C₁-C₆ alkyl substituted with 0-1 R^(11a);    -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(11b);-   alternatively, two R¹¹ substituents on the same or adjacent carbon    atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused    radical;-   R^(11a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl    substituted with 0-3 R^(11b);    -   R^(11b), at each occurrence, is independently selected from H,        OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄        alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy;-   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl);-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl);-   R¹⁷ is H, aryl, (aryl)CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl;-   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl); and-   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and    —S(═O)₂—(C₁-C₆ alkyl); and-   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or    phenethyl.

In a further preferred embodiment the present invention provides

-   R³ is —(CR⁷R^(7a))_(n)—R⁴,    -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or    -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴;-   n is 0 or 1;-   m is 0 or 1;-   R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, or butoxy;-   R⁴ is H, OH,    -   C₁-C₄ alkyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkynyl substituted with 0-1 R^(4a),    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from is H, F,    Cl, CF₃,    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b), phenyl substituted        with 0-3 R^(4b), or    -   5 to 6 membered heterocycle substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂    haloalkoxy;-   R⁵ is H, OR¹⁴;    -   C₁-C₄ alkyl substituted with 0-3 R^(5b);    -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or    -   C₂-C₄ alkynyl substituted with 0-2 R^(5b);-   R^(5a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, butoxy, or allyl;-   R^(5b), at each occurrence, is independently selected from:    -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);    -   phenyl substituted with 0-3 R^(5c); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂    haloalkoxy;-   R⁶ is H;-   R⁷, at each occurrence, is independently selected from H, F, CF₃,    methyl, and ethyl;-   R^(7a), at each occurrence, is independently selected from H, F,    CF₃, methyl, and ethyl;-   R^(7b) is independently selected from H, methyl, and ethyl;-   W is a bond, —CH₂—, —CH(CH₃)—, —CH₂CH₂— or —CH(CH₃)CH₂—;-   X is a bond;    -   phenyl substituted with 0-2 R^(Xb);    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,    C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,    or —N(CH₂CH₃)—,-   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,    C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   B is a seven membered lactam,    -   wherein the lactam is saturated, partially saturated or        unsaturated;    -   wherein each additional lactam carbon is substituted with 0-2        R¹¹; and,    -   optionally, the lactam contains a heteroatom selected from —O—,        —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—;-   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷;    -   C₁-C₄ alkyl substituted with 0-1 R^(10a);    -   phenyl substituted with 0-4 R^(10b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(10b); or    -   5 to 6 membered heterocycle optionally substituted with 0-3        R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₄    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl    substituted with 0-4 R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    C₁-C₄ alkyl, C₁-C₃ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃;-   R¹¹, at each occurrence, is independently selected from    -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, CF₃;    -   C₁-C₄ alkyl substituted with 0-1 R^(11a);    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 6 membered heterocycle substituted with 0-3 R^(11b);-   alternatively, two R¹¹ substituents on the same or adjacent carbon    atoms may be combined to form a cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, or a benzo fused radical;-   R^(11a), at each occurrence, is independently selected from H, C₁-C₄    alkyl, OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3    R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   R¹⁴ is H, phenyl, benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₄    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄    alkyl);-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄    alkyl);-   R¹⁷ is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl,    4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl,    (4-methylphenyl) methyl, (4-trifluorophenyl) methyl, methyl, ethyl,    propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or    ethoxyethyl;-   R¹⁸, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and-   R¹⁹, at each occurrence, is independently selected from H, methyl,    and ethyl.

[5] In a more preferred embodiment the present invention provides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein:-   R³ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,    -   —CH₂(CH₃)₂, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃,    -   —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃,    -   —CH═CH₂, —CH₂CH═CH₂, —CH₂C(CH₃)═CH₂, —CH₂CH═C(CH₃)₂,        —CH₂CH₂CH═CH₂, —CH₂CH₂C(CH₃)═CH₂, —CH₂CH₂CH═C(CH₃)₂,        cis-CH₂CH═CH(CH₃), cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃),        trans-CH₂CH₂CH═CH(CH₃);    -   —C≡CH, —CH₂C≡CH, —CH₂C≡C(CH₃),    -   cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,        cyclohexyl-CH₂—, cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—,        cyclopentyl-CH₂CH₂—, cyclohexyl-CH₂CH₂—,    -   phenyl-CH₂—,    -   (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—,        (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂—,    -   (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—,    -   (2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—,    -   (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,    -   (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—,    -   (2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—,    -   (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,    -   (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—,    -   (3-Cl-4-F-phenyl)CH₂—,    -   phenyl-CH₂CH₂—,    -   (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—,    -   (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—,    -   (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—,    -   (2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—,    -   (2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—,    -   (3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—,    -   (2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—,    -   (2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—,    -   (3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—,    -   (3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—, or-   R⁵ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂(CH₃)₂, —CH₂CH₂CH₂CH₃,    -   —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃,    -   —CH₂CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₂CH₃,    -   —CH₂CH(CH₃)CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH(CH₂CH₃)₂, —CF₃, —CH₂CF₃,        —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃,    -   —CH₂CH₂CH₂CH₂CF₃, —CH═CH₂, —CH₂CH═CH₂, —CH═CHCH₃,        cis-CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃), trans-CH₂CH═CH(C₆H₅),        —CH₂CH═C(CH₃)₂, cis-CH₂CH═CHCH₂CH₃,    -   trans-CH₂CH═CHCH₂CH₃, cis-CH₂CH₂CH═CH(CH₃),        trans-CH₂CH₂CH═CH(CH₃), trans-CH₂CH═CHCH₂(C₆H₅),    -   —C≡CH, —CH₂C≡CH, —CH₂C≡C(CH₃), —CH₂C≡C(C₆H₅)    -   —CH₂CH₂C≡CH, —CH₂CH₂C≡C(CH₃), —CH₂CH₂C≡C(C₆H₅)    -   —CH₂CH₂CH₂C≡CH, —CH₂CH₂CH₂C≡C(CH₃), —CH₂CH₂CH₂C≡C(C₆H₅)    -   cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,        cyclohexyl-CH₂—, (2-CH₃-cyclopropyl)CH₂—,    -   (3-CH₃-cyclobutyl)CH₂—,    -   cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—,    -   cyclopentyl-CH₂CH₂—, cyclohexyl-CH₂CH₂—,    -   (2-CH₃-cyclopropyl)CH₂CH₂—, (3-CH₃-cyclobutyl)CH₂CH₂—,    -   phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—,    -   (4-F-phenyl)CH₂—, furanyl-CH₂—, thienyl-CH₂—,    -   pyridyl-CH₂—, 1-imidazolyl-CH₂—, oxazolyl-CH₂—,    -   isoxazolyl-CH₂—,    -   phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—,    -   (4-F-phenyl)CH₂CH₂—, furanyl-CH₂CH₂—, thienyl-CH₂CH₂—,    -   pyridyl-CH₂CH₂—, 1-imidazolyl-CH₂CH₂—, oxazolyl-CH₂CH₂—,    -   isoxazolyl-CH₂CH₂—,-   W is a bond, —CH₂—, or —CH(CH₃)—;-   X is a bond;-   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—;-   V is a bond, —C—(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, or    —N(CH₃)—,-   Z is phenyl 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl,    3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl,    2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl,    2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl,    3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl,    3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl,    2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl,    4-MeS-phenyl, 2-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl, furanyl,    thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl,    1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, morpholino,N-piperinyl,    phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—,    (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂—,    (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—,    (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,    (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—,    (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,    (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl-4-F-phenyl)CH₂—,    (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—, (4-MeO-phenyl)CH₂—,    (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—, (4-Me-phenyl)CH₂—,    (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—, 4-MeS-phenyl)CH₂—,    (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—, (4-CF₃O-phenyl)CH₂—,    (furanyl)CH₂—,(thienyl)CH₂—, (pyridyl)CH₂—, (2-Me-pyridyl)CH₂—,    (3-Me-pyridyl)CH₂—, (4-Me-pyridyl)CH₂—, (1-imidazolyl)CH₂—,    (oxazolyl)CH₂—, (isoxazolyl)CH₂—, (1-benzimidazolyl)CH₂—,    (cyclopropyl)CH₂—, (cyclobutyl)CH₂—, (cyclopentyl)CH₂—,    (cyclohexyl)CH₂—, (morpholino)CH₂—, (N-pipridinyl)CH₂—,    phenyl-CH₂CH₂—, (phenyl)₂CHCH₂—, (2-F-phenyl)CH₂CH₂—,    (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—,    (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—,    (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—,    (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—,    (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—,    (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—,    (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—,    (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—,    (3-F-5-Cl-phenyl)CH₂CH₂—, (3-Cl-4-F-phenyl)CH₂CH₂—,    (2-MeO-phenyl)CH₂CH₂—, (3-MeO-phenyl)CH₂CH₂—, (4-MeO-phenyl)CH₂CH₂—,    (2-Me-phenyl)CH₂CH₂—, (3-Me-phenyl)CH₂CH₂—, (4-Me-phenyl)CH₂CH₂—,    (2-MeS-phenyl)CH₂CH₂—, (3-MeS-phenyl)CH₂CH₂—, (4-MeS-phenyl)CH₂CH₂—,    (2-CF₃O-phenyl)CH₂CH₂—, (3-CF₃O-phenyl)CH₂CH₂—,    (4-CF₃O-phenyl)CH₂CH₂—, (furanyl)CH₂CH₂—,(thienyl)CH₂CH₂—,    (pyridyl)CH₂CH₂—, (2-Me-pyridyl)CH₂CH₂—, (3-Me-pyridyl)CH₂CH₂—,    (4-Me-pyridyl)CH₂CH₂—, (imidazolyl)CH₂CH₂—, (oxazolyl)CH₂CH₂—,    (isoxazolyl)CH₂CH₂—, (benzimidazolyl)CH₂CH₂—,(cyclopropyl)CH₂CH₂—,    (cyclobutyl)CH₂CH₂—,(cyclopentyl)CH₂CH₂—,    (cyclohexyl)CH₂CH₂—,(morpholino)CH₂CH₂—, (N-pipridinyl)CH₂CH₂—,-   B is a seven membered lactam,    -   wherein the lactam is saturated, partially saturated or        unsaturated;    -   wherein each additional lactam carbon is substituted with 0-2        R¹¹; and,    -   optionally, the lactam contains a heteroatom selected from —O—,        —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—;-   R¹⁰ is H, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,    (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 4-Cl-phenyl,    (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl,    (4-CH₃-phenyl)CH₂—, (4-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl,    (4-CF₃-phenyl)CH₂—, or (4-CF₃-phenyl)CH₂CH₂—;-   R¹¹, at each occurrence, is independently selected from H, ═O,    methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,    (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 4-Cl-phenyl,    (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl,    (4-CH₃-phenyl)CH₂—, (4-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl,    (4-CF₃-phenyl)CH₂—, or (4-CF₃-phenyl)CH₂CH₂—; and-   alternatively, two R¹¹ substituents on the same or adjacent carbon    atoms may be combined to form a cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, or a benzo fused radical.

[6] In a further more preferred embodiment the present inventionprovides

-   B is

[7] In an even more preferred embodiment the present invention provides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein:-   R³ is R⁴,-   R⁴ is C₁-C₄ alkyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkynyl substituted with 0-2 R^(4a),-   R^(4a), at each occurrence, is independently selected from is H, F,    CF₃,    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),    -   phenyl substituted with 0-3 R^(4b), or    -   5 to 6 membered heterocycle substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   R⁵ is C₁-C₄ alkyl substituted with 0-3 R^(5b);    -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or    -   C₂-C₄ alkynyl substituted with 0-2 R^(5b);-   R^(5b), at each occurrence, is independently selected from:    -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);    -   phenyl substituted with 0-3 R^(5c); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   W is —CH₂—, or —CH(CH₃)—;-   X is a bond;    -   phenyl substituted with 0-2 R^(Xb);    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,    or —N(CH₂CH₃)—,-   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   R¹¹ is methoxy, ethoxy, propoxy, butoxy, Cl, F, ═O, NR¹⁸R¹⁹, CF₃;    -   C₁-C₄ alkyl substituted with 0-1 R^(11a);    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 6 membered heterocycle substituted with 0-3 R^(11b);-   alternatively, two R¹¹ substituents on the same or adjacent carbon    atoms may be combined to form a cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, or a benzo fused radical;-   R^(11a), at each occurrence, is independently selected from H, C₁-C₄    alkyl, OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3    R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, butyl;-   R¹⁵, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, and butyl;-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄    alkyl);-   R¹⁸, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and-   R¹⁹, at each occurrence, is independently selected from H, methyl,    and ethyl.

[8] In another even more preferred embodiment the present inventionprovides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein:-   R³ is R⁴,-   R⁴ is C₁-C₄ alkyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkynyl substituted with 0-2 R^(4a),-   R^(4a), at each occurrence, is independently selected from is H, F,    CF₃,    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),    -   phenyl substituted with 0-3 R^(4b), or    -   5 to 6 membered heterocycle substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   R⁵ is C₁-C₄ alkyl substituted with 0-3 R^(5b);    -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or    -   C₂-C₄ alkynyl substituted with 0-2 R^(5b);-   R^(5b), at each occurrence, is independently selected from:    -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);    -   phenyl substituted with 0-3 R^(5c); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   W is —CH₂—, or —CH(CH₃)—;-   X is a bond;    -   phenyl substituted with 0-2 R^(Xb);    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, N(CH₃)—, or    —N(CH₂CH₃)—,-   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷;    -   C₁-C₄ alkyl substituted with 0-1 R^(10a);    -   phenyl substituted with 0-4 R^(10b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(10b); or    -   5 to 6 membered heterocycle optionally substituted with 0-3        R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₄    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl    substituted with 0-4 R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br,    I, CN, NO₂, NR¹⁵R¹⁶, or CF₃;-   R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, butyl;-   R¹⁵, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, and butyl;-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄    alkyl); and-   R¹⁷ is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl,    4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl,    (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl,    propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or    ethoxyethyl.

[9] In another even more preferred embodiment the present inventionprovides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein:-   R³ is R⁴,-   R⁴ is C₁-C₄ alkyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkynyl substituted with 0-2 R^(4a),-   R^(4a), at each occurrence, is independently selected from is H, F,    CF₃,    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),    -   phenyl substituted with 0-3 R^(4b), or    -   5 to 6 membered heterocycle substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   R⁵ is C₁-C₄ alkyl substituted with 0-3 R^(5b);    -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or    -   C₂-C₄ alkynyl substituted with 0-2 R^(5b);-   R^(5b), at each occurrence, is independently selected from:    -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);    -   phenyl substituted with 0-3 R^(5c); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   W is —CH₂—, or —CH(CH₃)—;-   X is a bond;    -   phenyl substituted with 0-2 R^(Xb);    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,    or —N(CH₂CH₃)—,-   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   R¹¹ is methoxy, ethoxy, propoxy, butoxy, Cl, F, ═O, NR¹⁸R¹⁹, CF₃;    -   C₁-C₄ alkyl substituted with 0-1 R^(11a);    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 6 membered heterocycle substituted with 0-3 R^(11b);-   R^(11a), at each occurrence, is independently selected from H, C₁-C₄    alkyl, OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3    R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, butyl;-   R¹⁵, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, and butyl;-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄    alkyl);-   R¹⁸, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and-   R¹⁹, at each occurrence, is independently selected from H, methyl,    and ethyl.

[10] In another even more preferred embodiment the present inventionprovides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein:-   R³ is R⁴,-   R⁴ is C₁-C₄ alkyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkynyl substituted with 0-1 R^(4a),-   R^(4a), at each occurrence, is independently selected from is H, F,    CF₃,    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),    -   phenyl substituted with 0-3 R^(4b), or    -   5 to 6 membered heterocycle substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   R⁵ is C₁-C₄ alkyl substituted with 0-3 R^(5b);    -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or    -   C₂-C₄ alkynyl substituted with 0-2 R^(5b);-   R^(5b), at each occurrence, is independently selected from:    -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);    -   phenyl substituted with 0-3 R^(5c); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   W is —CH₂—, or —CH(CH₃)—;-   X is a bond;    -   phenyl substituted with 0-2 R^(Xb);    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,    or —N(CH₂CH₃)—,-   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, butyl;-   R¹⁵, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, and butyl; and-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄    alkyl).

[11] In another preferred embodiment the present invention provides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein:-   R³ is —(CR⁷R^(7a))_(n)—R⁴,    -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)_R⁴,    -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or    -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴;-   n is 0, 1, or 2;-   m is 0, 1, or 2;-   R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, or butoxy;-   R⁴ is H, OH, OR^(14a),    -   C₁-C₄ alkyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkynyl substituted with 0-2 R^(4a),    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from is    -   H, F, Cl, Br, I CF₃,    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   R⁵ is H, OR¹⁴;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle substituted with 0-3R^(5c);-   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄    alkenyloxy;-   R^(5b), at each occurrence, is independently selected from:    -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   R⁶ is H, methyl, or ethyl;-   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,    Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl;-   R^(7a), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO2, CF₃, phenyl and C₁-C₄ alkyl;-   R^(7b) is independently selected from H. methyl, ethyl, propyl, and    butyl;-   W is (CR⁸R^(8a))_(p)—;-   p is 0, 1, or 2;-   R⁸ and R^(8a), at each occurrence, are independently selected from    H, F, C₁-C₃ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl and C₃-C₆    cycloalkyl;-   X is a bond;    -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);    -   C₃-C₁₀ carbocycle substituted with 0-2 R^(Xb); or    -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—;-   t is 0, 1, or 2;-   u is 0, 1, or 2;-   R⁹ and R^(9a), at each occurrence, are independently selected from    H, F, C₁-C₄ alkyl or C₃-C₆ cycloalkyl;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,    —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,    —S(═O)₂NR^(19b)—, NR^(19b)S(═O)—, or —S(═O)NR^(19b)—;-   Z is C₁-C₃ alkyl substituted with 1-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   B is a seven membered lactam,    -   wherein the lactam is saturated, partially saturated or        unsaturated;    -   wherein each additional lactam carbon is substituted with 0-2        R¹¹; and,    -   optionally, the lactam contains a heteroatom selected from —O—,        —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—;-   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,    S(═O)₂R¹⁷;    -   C₁-C₆ alkyl substituted with 0-1 R^(10a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or    -   5 to 10 membered heterocycle optionally substituted with 0-3        R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl    substituted with 0-4 R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃;-   R¹¹, at each occurrence, is independently selected from    -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷,        C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;    -   C₁-C₆ alkyl substituted with 0-1 R^(11a);    -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(11b);-   alternatively, two R¹¹ substituents on the same or adjacent carbon    atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused    radical;-   R^(11a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl    substituted with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,    C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy;-   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl);-   R¹⁶ at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl);-   R¹⁷ is H, aryl, (aryl)CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl;-   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl); and-   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and    —S(═O)₂—(C₁-C₆ alkyl); and-   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or    phenethyl.

[12] In a more preferred embodiment the present invention provides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein:-   R³ is R⁴,-   n is 0 or 1;-   m is 0 or 1;-   R⁴ is H, OH,    -   C₁-C₄ alkyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkynyl substituted with 0-1 R^(4a),    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from is    -   H, F, Cl, CF₃,    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),    -   phenyl substituted with 0-3 R^(4b), or    -   5 to 6 membered heterocycle substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂    haloalkoxy;-   R⁵ is H, OR¹⁴;    -   C₁-C₄ alkyl substituted with 0-3 R^(5b);    -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or    -   C₂-C₄ alkynyl substituted with 0-2 R^(5b);-   R^(5b), at each occurrence, is independently selected from:    -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);    -   phenyl substituted with 0-3 R^(5c); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂    haloalkoxy;-   W is a bond, —CH₂—, —CH(CH₃)—, —CH₂CH₂— or —CH(CH₃)CH₂—;-   X is a bond;    -   phenyl substituted with 0-2 R^(Xb);    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,    C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,    or —N(CH₂CH₃)—,-   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,    C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   B is a seven membered lactam,    -   wherein the lactam is saturated, partially saturated or        unsaturated;    -   wherein each additional lactam carbon is substituted with 0-2        R¹¹; and,    -   optionally, the lactam contains a heteroatom selected from —O—,        —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—;-   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷;    -   C₁-C₄ alkyl substituted with 0-1 R^(10a);    -   phenyl substituted with 0-4 R^(10b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(10b); or    -   5 to 6 membered heterocycle optionally substituted with 0-3        R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₄    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl    substituted with 0-4 R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    C₁-C₄ alkyl, C₁-C₃ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃;-   R¹¹, at each occurrence, is independently selected from    -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, CF₃;    -   C₁-C₄ alkyl substituted with 0-1 R^(11a);    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 6 membered heterocycle substituted with 0-3 R^(11b);-   alternatively, two R¹¹ substituents on the same or adjacent carbon    atoms may be combined to form a cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, or a benzo fused radical;-   R^(11a), at each occurrence, is independently selected from H, C₁-C₄    alkyl, OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3    R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   R¹⁴ is H, phenyl, benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₄    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄    alkyl);-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄    alkyl);-   R¹⁷ is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl,    4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl,    (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl,    propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or    ethoxyethyl;-   R¹⁸, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and-   R¹⁹, at each occurrence, is independently selected from H, methyl,    and ethyl.

[13] In an even more preferred embodiment the present invention provides

-   B is

[14] In a preferred embodiment the present provides

-   A is S;-   Q is —NR¹R²;-   R¹, at each occurrence, is independently selected from:    -   H;    -   C₁-C₆ alkyl substituted with 0-3 R^(1a);    -   C₂-C₆ alkenyl substituted with 0-3 R^(1a);-   R^(1a), at each occurrence, is independently selected from H, OR¹⁴,    F, ═O, NR¹⁵R¹⁶, CF₃;    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(1b);    -   phenyl substituted with 0-3 R^(1b); and    -   5 to 6 membered heterocycle substituted with 0-3 R^(1b);-   R^(1b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy,    C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy;-   R² is independently selected from H, NH₂, OH, C₁-C₆ alkyl, C₁-C₆    alkoxy, phenoxy, and benzyloxy;-   R³ is —(CR⁷R^(7a))_(n)—R⁴,    -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—S (═O)—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—S(═O)₂—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—C(═O)—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—NHC(═O)—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—C(═O)NH—(CR⁷R^(7a))_(m)—R⁴,    -   (CR⁷R^(7a))_(n)—NHS(═O)₂—(CR⁷R^(7a))_(m)—R⁴, or    -   —(CR⁷R^(7a))_(n), —S(═O) 2NH—(CR⁷R^(7a))_(m)—R⁴;-   n is 0, 1, 2, or 3;-   m is 0, 1, 2, or 3;-   R^(3a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₂-C₄ alkenyloxy;-   R⁴ is H, OH, OR^(14a),    -   C₁-C₆ alkyl substituted with 0-3 R^(4a),    -   C₂-C₆ alkenyl substituted with 0-3 R^(4a),    -   C₂-C₆ alkynyl substituted with 0-3 R^(4a),    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from is H, F,    Cl, Br, I, CF₃,    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   R⁵ is H, OR¹⁴;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₁-C₆ alkoxy substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle substituted with 0-3R^(5c);-   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄    alkenyloxy;-   R^(5b), at each occurrence, is independently selected from:    -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   R⁶ is H;    -   C₁-C₆ alkyl substituted with 0-3 R^(6a);    -   C₃-C₆ carbocycle substituted with 0-3 R^(6b); or    -   C₆-C₁₀ aryl substituted with 0-3R^(6b);-   R^(6a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, phenyl or CF₃;-   R^(6b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,    C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy;-   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,    Br, I, CN, NO2, CF₃, and C₁-C₄ alkyl;-   R^(7a), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO2, CF₃, aryl and C₁-C₄ alkyl;-   R^(7b) is independently selected from H and C₁-C₄ alkyl;-   W is —(CR⁸R^(8a))_(p)—;-   p is 0, 1, 2, 3, or 4;-   R⁸ and R^(8a), at each occurrence, are independently selected from    H, F, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl and C₃-C₈    cycloalkyl;-   X is a bond;    -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(Xb); or    -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—;-   t is 0, 1, 2, or 3;-   u is 0, 1, 2, or 3;-   R⁹ and R^(9a), at each occurrence, are independently selected from    H, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,    —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,    —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or    —OC(═O)—;-   Z is C₁-C₃ alkyl substituted with 1-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   B is a 6, 7, or 8 membered thiolactam,    -   wherein the thiolactam is saturated, partially saturated or        unsaturated;    -   wherein each additional thiolactam carbon is substituted with        0-2 R¹¹; and,    -   optionally, the thiolactam contains a heteroatom selected from        —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—;-   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,    S(═O)₂R¹⁷;    -   C₁-C₆ alkyl substituted with 0-1 R^(10a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or    -   5 to 10 membered heterocycle optionally substituted with 0-3        R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl    substituted with 0-4 R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃;-   R¹¹, at each occurrence, is independently selected from    -   C₁-C₄ alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷,        C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;    -   C₁-C₆ alkyl substituted with 0-1 R^(11a);    -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(11b);-   alternatively, two R¹¹ substituents on the same or adjacent carbon    atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused    radical;-   R^(11a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl    substituted with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,    C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy;-   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl);-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl);-   R¹⁷ is H, aryl, (aryl)CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl;-   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl); and-   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and    —S(═O)₂—(C₁-C₆ alkyl); and-   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or    phenethyl.

[15] In a further preferred embodiment the present invention provides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein:-   R³ is —(CR⁷R^(7a))_(n)—R⁴,    -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or    -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴;-   n is 0, 1, or 2;-   m is 0, 1, or 2;-   R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, or butoxy;-   R⁴ is H, OH, OR^(14a),    -   C₁-C₄ alkyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkynyl substituted with 0-2 R^(4a),    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from is    -   H, F, Cl, Br, I CF₃,    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   R⁵ is H, OR¹⁴;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle substituted with 0-3R^(5c);-   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄    alkenyloxy;-   R^(5b), at each occurrence, is independently selected from:    -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   R⁶ is H, methyl, or ethyl;-   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,    Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl;-   R^(7a), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, CF₃, phenyl and C₁-C₄ alkyl;-   R^(7b) is independently selected from H. methyl, ethyl, propyl, and    butyl;-   W is —(CR⁸R^(8a))_(p)—;-   p is 0, 1, or 2;-   R⁸ and R^(8a), at each occurrence, are independently selected from    H, F, C₁-C₃ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl and C₃-C₆    cycloalkyl;-   X is a bond;    -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);    -   C₃-C₁₀ carbocycle substituted with 0-2 R^(Xb); or    -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—;-   t is 0, 1, or 2;-   u is 0, 1, or 2;-   R⁹ and R^(9a), at each occurrence, are independently selected from    H, F, C₁-C₄ alkyl or C₃-C₆ cycloalkyl;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,    —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,    —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, or —S(═O)NR^(19b)—;-   Z is C₁-C₃ alkyl substituted with 1-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄    haloalkoxy;-   B is a seven membered thiolactam,    -   wherein the thiolactam is saturated, partially saturated or        unsaturated;    -   wherein each additional thiolactam carbon is substituted with        0-2 R¹¹; and,    -   optionally, the thiolactam contains a heteroatom selected from        —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—;-   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,    S(═O)₂R¹⁷;    -   C₁-C₆ alkyl substituted with 0-1 R^(10a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or    -   5 to 10 membered heterocycle optionally substituted with 0-3        R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl    substituted with 0-4 R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃;-   R¹¹, at each occurrence, is independently selected from    -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷,        C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;    -   C₁-C₆ alkyl substituted with 0-1 R^(11a);    -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(11b);-   alternatively, two R¹¹ substituents on the same or adjacent carbon    atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused    radical;-   R^(11a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl    substituted with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,    C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy;-   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl);-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl);-   R¹⁷ is H, aryl, (aryl)CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl;-   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆    alkyl); and-   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and    —S(═O)₂—(C₁-C₆ alkyl); and-   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or    phenethyl.

[16] In a further preferred embodiment the present invention provides

-   R³ is —(CR⁷R^(7a))_(n)—R⁴,    -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,    -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or    -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴;-   n is 0 or 1;-   m is 0 or 1;-   R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, or butoxy;-   R⁴ is H, OH,    -   C₁-C₄ alkyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkynyl substituted with 0-1 R^(4a),    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),    -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or    -   5 to 10 membered heterocycle substituted with 0-3 R^(4b);-   R^(4a), at each occurrence, is independently selected from is    -   H, F, Cl, CF₃,    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),    -   phenyl substituted with 0-3 R^(4b), or    -   5 to 6 membered heterocycle substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂    haloalkoxy;-   R⁵ is H, OR¹⁴;    -   C₁-C₄ alkyl substituted with 0-3 R^(5b);    -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or    -   C₂-C₄ alkynyl substituted with 0-2 R^(5b);-   R^(5a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, butoxy, or allyl;-   R^(5b), at each occurrence, is independently selected from:    -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);    -   phenyl substituted with 0-3 R^(5c); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂    haloalkoxy;-   R⁶ is H;-   R⁷, at each occurrence, is independently selected from H, F, CF₃,    methyl, and ethyl;-   R^(7a), at each occurrence, is independently selected from H, F,    CF₃, methyl, and ethyl;-   R^(7b) is independently selected from H, methyl, and ethyl;-   W is a bond, —CH₂—, —CH(CH₃)—, —CH₂CH₂— or —CH(CH₃)CH₂—;-   X is a bond;    -   phenyl substituted with 0-2 R^(Xb);    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,    C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,    or —N(CH₂CH₃)—,-   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or    -   5 to 10 membered heterocycle substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,    C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   B is a seven membered thiolactam,    -   wherein the thiolactam is saturated, partially saturated or        unsaturated;    -   wherein each additional thiolactam carbon is substituted with        0-2 R¹¹; and,    -   optionally, the thiolactam contains a heteroatom selected from        —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—;-   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷;    -   C₁-C₄ alkyl substituted with 0-1 R^(10a);    -   phenyl substituted with 0-4 R^(10b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(10b); or    -   5 to 6 membered heterocycle optionally substituted with 0-3        R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₄    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl    substituted with 0-4 R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    C₁-C₄ alkyl, C₁-C₃ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃;-   R¹¹, at each occurrence, is independently selected from    -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, CF₃;    -   C₁-C₄ alkyl substituted with 0-1 R^(11a);    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 6 membered heterocycle substituted with 0-3 R^(11b);-   alternatively, two R¹¹ substituents on the same or adjacent carbon    atoms may be combined to form a cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, or a benzo fused radical;-   R^(11a), at each occurrence, is independently selected from H, C₁-C₄    alkyl, OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3    R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   R¹⁴ is H, phenyl, benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₄    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄    alkyl);-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄    alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄    alkyl);-   R¹⁷ is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl,    4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl,    (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl,    propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or    ethoxyethyl;-   R¹⁸, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and-   R¹⁹, at each occurrence, is independently selected from H, methyl,    and ethyl.

[17] In a more preferred embodiment the present invention provides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein:-   R³ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂(CH₃)₂,    —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CF₃, —CH₂CF₃,    —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH═CH₂, —CH₂CH═CH₂, —CH₂C(CH₃)═CH₂,    —CH₂CH═C(CH₃)₂, —CH₂CH₂CH═CH₂, —CH₂CH₂C(CH₃)═CH₂, —CH₂CH₂CH═C(CH₃)₂,    cis-CH₂CH═CH(CH₃), cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃),    trans-CH₂CH₂CH═CH(CH₃);    -   —C≡CH, —CH₂C≡CH, —CH₂C≡(CH₃), cyclopropyl-CH₂—, cyclobutyl-CH₂—,        cyclopentyl-CH₂—, cyclohexyl-CH₂—, cyclopropyl-CH₂CH₂—,        cyclobutyl-CH₂CH₂—, cyclopentyl-CH₂CH₂—, cyclohexyl-CH₂CH₂—,        phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—,        (4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—,        (4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—,        (2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—,        (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,        (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—,        (2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—,        (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,        (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—,        (3-Cl-4-F-phenyl)CH₂—, phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—,        (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—,        (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—,        (2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—,        (2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—,        (3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—,        (2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—,        (2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—,        (3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—,        (3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—, or-   R⁵ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂(CH₃)₂, —CH₂CH₂CH₂CH₃,    —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CH₂CH₂CH₂CH₂CH₃,    —CH(CH₃)CH₂CH₂CH₃, —CH₂CH(CH₃)CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH(CH₂CH₃)₂,    —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂CH₂CF₃, —CH═CH₂,    —CH₂CH═CH₂, —CH═CHCH₃, cis-CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃),    trans-CH₂CH═CH(C₆H₅), —CH₂CH═C(CH₃)₂, cis-CH₂CH═CHCH₂CH₃,    trans-CH₂CH═CHCH₂CH₃, cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH₂CH═CH(CH₃),    trans-CH₂CH═CHCH₂(C₆H₅), —C≡CH, —CH₂C≡CH, —CH₂C≡C(CH₃),    —CH₂C≡C(C₆H₅) —CH₂CH₂C≡CH, —CH₂CH₂C≡C(CH₃), —CH₂CH₂C≡C(C₆H₅)    —CH₂CH₂CH₂C≡CH, —CH₂CH₂CH₂C≡C(CH₃), —CH₂CH₂CH₂C≡C(C₆H₅)    cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,    cyclohexyl-CH₂—, (2-CH₃-cyclopropyl)CH₂—, (3-CH₃-cyclobutyl)CH₂—,    cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—, cyclopentyl-CH₂CH₂—,    cyclohexyl-CH₂CH₂—, (2-CH₃-cyclopropyl)CH₂CH₂—,    (3-CH₃-cyclobutyl)CH₂CH₂—, phenyl-CH₂—, (2-F-phenyl)CH₂—,    (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, furanyl-CH₂—, thienyl-CH₂—,    pyridyl-CH₂—, 1-imidazolyl-CH₂—, oxazolyl-CH₂—, isoxazolyl-CH₂—,    phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—,    (4-F-phenyl)CH₂CH₂—, furanyl-CH₂CH₂—, thienyl-CH₂CH₂—,    pyridyl-CH₂CH₂—, 1-imidazolyl-CH₂CH₂—, oxazolyl-CH₂CH₂—,    isoxazolyl-CH₂CH₂—,-   W is a bond, —CH₂—, or —CH(CH₃)—;-   X is a bond;-   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, or    —N(CH₃)—,-   Z is phenyl 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl,    3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl,    2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl,    2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl,    3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl,    3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl,    2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl,    4-MeS-phenyl, 2-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl, furanyl,    thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl,    1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, morpholino,N-piperinyl,    phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—,    (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂—,    (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—,    (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,    (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—,    (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,    (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl-4-F-phenyl)CH₂—,    (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—, (4-MeO-phenyl)CH₂—,    (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—, (4-Me-phenyl)CH₂—,    (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—, 4-MeS-phenyl)CH₂—,    (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—, (4-CF₃O-phenyl)CH₂—,    (furanyl)CH₂—,(thienyl)CH₂—, (pyridyl)CH₂—, (2-Me-pyridyl)CH₂—,    (3-Me-pyridyl)CH₂—, (4-Me-pyridyl)CH₂—, (1-imidazolyl)CH₂—,    (oxazolyl)CH₂—, (isoxazolyl)CH₂—, (1-benzimidazolyl)CH₂—,    (cyclopropyl)CH₂—, (cyclobutyl)CH₂—, (cyclopentyl)CH₂—,    (cyclohexyl)CH₂—, (morpholino)CH₂—, (N-pipridinyl)CH₂—,    phenyl-CH₂CH₂—, (phenyl)₂CHCH₂—, (2-F-phenyl)CH₂CH₂—,    (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—,    (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—,    (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—,    (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—,    (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—,    (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—,    (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—,    (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—,    (3-F-5-Cl-phenyl)CH₂CH₂—, (3-Cl-4-F-phenyl)CH₂CH₂—,    (2-MeO-phenyl)CH₂CH₂—, (3-MeO-phenyl)CH₂CH₂—, (4-MeO-phenyl)CH₂CH₂—,    (2-Me-phenyl)CH₂CH₂—, (3-Me-phenyl)CH₂CH₂—, (4-Me-phenyl)CH₂CH₂—,    (2-MeS-phenyl)CH₂CH₂—, (3-MeS-phenyl)CH₂CH₂—, (4-MeS-phenyl)CH₂CH₂—,    (2-CF₃O-phenyl)CH₂CH₂—, (3-CF₃O-phenyl)CH₂CH₂—,    (4-CF₃O-phenyl)CH₂CH₂—, (furanyl)CH₂CH₂—,(thienyl)CH₂CH₂—,    (pyridyl)CH₂CH₂—, (2-Me-pyridyl)CH₂CH₂—, (3-Me-pyridyl)CH₂CH₂—,    (4-Me-pyridyl)CH₂CH₂—, (imidazolyl)CH₂CH₂—, (oxazolyl)CH₂CH₂—,    (isoxazolyl)CH₂CH₂—, (benzimidazolyl)CH₂CH₂—,(cyclopropyl)CH₂CH₂—,    (cyclobutyl)CH₂CH₂—,(cyclopentyl)CH₂CH₂—,    (cyclohexyl)CH₂CH₂—,(morpholino)CH₂CH₂—, (N-pipridinyl)CH₂CH₂—,-   B is a seven membered thiolactam,    -   wherein the thiolactam is saturated, partially saturated or        unsaturated;    -   wherein each additional thiolactam carbon is substituted with        0-2 R¹¹; and,    -   optionally, the thiolactam contains a heteroatom selected from        —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—;-   R¹⁰ is H, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,    (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 4-Cl-phenyl,    (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl,    (4-CH₃-phenyl)CH₂—, (4-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl,    (4-CF₃-phenyl)CH₂—, or (4-CF₃-phenyl)CH₂CH₂—;-   R¹¹, at each occurrence, is independently selected from H, ═O,    methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,    (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 4-Cl-phenyl,    (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl,    (4-CH₃-phenyl)CH₂—, (4-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl,    (4-CF₃-phenyl)CH₂—, or (4-CF₃-phenyl)CH₂CH₂—; and-   alternatively, two R¹¹ substituents on the same or adjacent carbon    atoms may be combined to form a cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, or a benzo fused radical.

[18] In a futher more preferred embodiment the present inventionprovides

-   B is

[19] In another even more preferred embodiment the present inventionprovides compounds of Formula (I) selected from:

-   -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(4-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2S,3R)        N1-[(3S)-hexahydro-1-(3-(2-tetrazolylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(propyl)-3-(2-methylpropyl)-butanediamide;    -   (2S,3R)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(propyl)-3-(2-methylpropyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;        and    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(phenethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-((4-fluorophenyl)methyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclopropylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclobutylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclopentylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclohexylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclopropylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclobutylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclopentylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclohexylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(phenethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-((4-fluorophenyl)methyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclopropylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclobutylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclopentylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclohexylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclopropylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclobutylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclopentylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclohexylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(phenethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-((4-fluorophenyl)methyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclopropylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclobutylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclopentylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclohexylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclopropylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclobutylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclopentylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;        and    -   (2R,3S)        N1-[(3S)-hexahydro-1-(cyclohexylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.

[20] In another even more preferred embodiment the present inventionprovides compounds of Formula (I) selected from:

-   -   (2R,3S)        N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;        and    -   (2R,3S)        N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;.        (2R,3S)        N1-[1,3-dihydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;        and    -   (2R,3S)        N1-[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.

[21] In another even more preferred embodiment the present inventionprovides compounds of Formula (I) selected from:

-   -   (2R,3S)        N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxp-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;        and    -   (2R,3S)        N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide.        (2R,3S)        N1-[6,7-dihydro-5-(benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(phenethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-((4-fluorophenyl)methyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclopropylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclobutylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclopentylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclohexylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclopropylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclobutylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclopentylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclohexylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(phenethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-((4-fluorophenyl)methyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclopropylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclobutylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclopentylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclohexylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclopropylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclobutylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclopentylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclohexylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(phenethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-((4-fluorophenyl)methyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclopropylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclobutylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclopentylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclohexylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclopropylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclobutylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclopentylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;        and    -   (2R,3S)        N1-[6,7-dihydro-5-(cyclohexylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.

[22] In another even more preferred embodiment the present inventionprovides compounds of Formula (I) selected from:

-   -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)N        1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)N        1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;        and    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;        and    -   (2R,3S)        N1-[1,3,4,5-tetrahydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.

[23] In another even more preferred embodiment the present inventionprovides compounds of Formula (I) selected from:

-   -   (2R,3S)        N1-[(3S)-hexahydro-1-(3,3-diphenylpropyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(phenyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(methyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(methoxy)-N-4-(methyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(methoxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(amino)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(allyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(3-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(butyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(2-furylmethyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide;    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(cyclopentyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide;        and    -   (2R,3S)        N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(cinnamyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide.

In another preferred embodiment of the present invention, Q is N(OH)H.

In another preferred embodiment of the present invention, Q is NH₂.

In another preferred embodiment

-   R³ is R⁴,-   R^(3a) is H, methyl, ethyl, propyl, or butyl;-   R⁴ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl-   R⁵ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl-   R^(5a) is H, methyl, ethyl, propyl, or butyl; and-   the total number of carbon atoms in R³, R^(3a), R⁵ and R^(5a)equals    seven or more.

In another preferred embodiment

-   R³ is R⁴;-   R^(3a) is H;-   R⁴ is C₁-C₄ alkyl substituted with 1-2 R^(4a),-   R^(4a), at each occurrence, is independently selected from C₃-C₆    cycloalkyl substituted with 0-3 R^(4b), phenyl substituted with 0-3    R^(4b), or 5 to 6 membered heterocycle substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   R⁵ is C₂-C₄ alkyl substituted with 0-3 R^(5b);    -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or    -   C₂-C₄ alkynyl substituted with 0-2 R^(5b);-   R^(5b), at each occurrence, is independently selected from:    -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);    -   phenyl substituted with 0-3 R^(5c); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); and-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy.

In another preferred embodiment

-   R³ is R⁴;-   R^(3a) is H;-   R⁴ is C₂-C₄ alkyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),    -   C₂-C₄ alkynyl substituted with 0-2 R^(4a),-   R^(4a), at each occurrence, is independently selected from is    -   H, F, CF₃,    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),    -   phenyl substituted with 0-3 R^(4b), or    -   5 to 6 membered heterocycle substituted with 0-3 R^(4b);-   R^(4b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   R⁵ is C₁-C₄ alkyl substituted with 1-2 R^(5b);-   R^(5b), at each occurrence, is independently selected from:    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);    -   phenyl substituted with 0-3 R^(5c); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); and-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy.

In another preferred embodiment

-   W is —(CH₂)_(p)—;-   p is 1, 2, or 3;-   X is a bond;    -   phenyl substituted with 0-2 R^(Xb);    -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb);    -   wherein the 5 to 6 membered heterocycle does not contain an oxo        or imino substituted ring atom; and-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy.

In another preferred embodiment when R¹ is H, R² is hydroxy, and R¹¹ isH, then X is not a bond.

It is understood that any and all embodiments of the present inventionmay be taken in conjunction with any other embodiment to describeadditional even more preferred embodiments of the present invention.

In a second embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier.

In a third embodiment, the present invention provides a method for thetreatment of neurological disorders associated with β-amyloid productioncomprising administering to a host in need of such treatment atherapeutically effective amount of a compound of Formula (I).

In a preferred embodiment the neurological disorder associated withβ-amyloid production is Alzheimer's Disease.

In a fourth embodiment, the present invention provides a method for thetreatment of neurological disorders associated with β-amyloid productioncomprising administering to a host in need of such treatment atherapeutically effective amount of a metalloprotease inhibitor whichinhibits γ-secretase activity.

In a preferred embodiment the neurological disorder associated withβ-amyloid production is Alzheimer's Disease.

In a preferred embodiment, the metalloprotease inhibitor is a hydroxamicacid.

In a more preferred embodiment, the metalloprotease inhibitor is ahydroxamic acid with an IC₅₀ value of less than 10 μM in the Aβimmunoprecipitation assay.

In a fifth embodiment, the present invention provides a method forinhibiting γ-secretase activity for the treatment of a physiologicaldisorder associated with inhibiting γ-secretase activity comprisingadministering to a host in need of such inhibition a therapeuticallyeffective amount of a compound of Formula (I) that inhibits γ-secretaseactivity.

In a preferred embodiment the physiological disorder associated withinhibiting γ-secretase activity is Alzheimer's Disease.

In a sixth embodiment, the present invention provides a compound ofFormula (I) for use in therapy.

In a preferred embodiment the present invention provides a compound ofFormula (I) for use in therapy of Alzheimer's Disease.

In a seventh embodiment, the present invention provides for the use of acompound of Formula (I) for the manufacture of a medicament for thetreatment of Alzheimer's Disease.

Definitions

As used herein, the term “Aβ” denotes the protein designated Aβ,β-amyloid peptide, and sometimes β/A4, in the art. Aβ is anapproximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acidsfound in amyloid plaques, the walls of meningeal and parenchymalarterioles, small arteries, capillaries, and sometimes, venules. Theisolation and sequence data for the first 28 amino acids are describedin U.S. Pat. No 4,666,829. The 43 amino acid sequence is:

1

Asp Ala Glu Phe Arg His Asp Ser Gly Tyr 11 Glu Val His His Gln Lys LeuVal Phe Phe 21 Ala Glu Asp Val Gly Ser Asn Lys Gly Ala 31 Ile Ile GlyLeu Met Val Gly Gly Val Val 41 Ile Ala Thr.However, a skilled artisan knows that fragments generated by enzymaticdegradation can result in loss of amino acids 1-10 and/or amino acids39-43. Thus, an amino acid sequence 1-43 represents the maximum sequenceof amino acids for Aβ peptide.

The term “APP”, as used herein, refers to the protein known in the artas b amyloid precursor protein. This protein is the precursor for Aβ andthrough the activity of “secretase” enzymes, as used herein, it isprocessed into Aβ. Differing secretase enzymes, known in the art, havebeen designated b secretase, generating the N-terminus of Aβ, asecretase cleaving around the 16/17 peptide bond in Aβ, and “γsecretases”, as used herein, generating C-terminal Aβ fragments endingat position 38, 39, 40, 41, 42, and 43 or generating C-terminal extendedprecursors which are subsequently truncated to the above polypeptides.

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

When any variable (e.g., R^(5b)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R^(5b), thensaid group may optionally be substituted with up to two R^(5b)groups andR^(5b) at each occurrence is selected independently from the definitionof R^(5b). Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “alkyl” or “alkylene” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms; for example, “C₁-C₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, butare not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl. Preferred “alkyl” group, unlessotherwise specified, is “C₁-C₄ alkyl”.

As used herein, “alkenyl” or “alkenylene” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more unsaturated carbon-carbon bonds which may occur in anystable point along the chain. Examples of “C₂-C₆ alkenyl” include, butare not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl,hexenyl, and the like.

As used herein, “alkynyl” or “alkynylene” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more carbon-carbon triple bonds which may occur in any stablepoint along the chain, such as ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, and the like.

“Alkoxy” or “alkyloxy” represents an alkyl group as defined above withthe indicated number of carbon atoms attached through an oxygen bridge.Examples of alkoxy include, but are not limited to, methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, ands-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, s-butoxy, t-butoxy. Similarly, “alkylthio” or“thioalkoxy” is represents an alkyl group as defined above with theindicated number of carbon atoms attached through a sulphur bridge.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo. Unless otherwise specified, preferred halo is fluoro and chloro.“Counterion” is used to represent a small, negatively charged speciessuch as chloride, bromide, hydroxide, acetate, sulfate, and the like.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen (for example—C_(v)F_(w) where v 1 to 3 and w=1 to (2v+1)). Examples of haloalkylinclude, but are not limited to, trifluoromethyl, trichloromethyl,pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl,2,2-difluoroethyl, heptafluoropropyl, and heptachloropropyl.“Haloalkoxy” is intended to mean a haloalkyl group as defined above withthe indicated number of carbon atoms attached through an oxygen bridge;for example trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy,and the like. “Halothioalkoxy” is intended to mean a haloalkyl group asdefined above with the indicated number of carbon atoms attached througha sulphur bridge.

“Cycloalkyl” is intended to include saturated ring groups, having thespecified number of carbon atoms. For example, “C₃-C₆ cycloalkyl”denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, “carbocycle” is intended to mean any stable 3- to7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic ortricyclic, any of which may be saturated, partially unsaturated, oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,[4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl,naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).Preferred “carbocycle” are cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

As used herein, the term “heterocycle” or “heterocyclic ring” isintended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7-to 14-membered bicyclic heterocyclic ring which is saturated partiallyunsaturated or unsaturated (aromatic), and which consists of carbonatoms and 1, 2, 3 or 4 heteroatoms, preferably 1, 2, or 3 heteroatoms,independently selected from the group consisting of N, O and S andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized. The heterocyclic ring may beattached to its pendant group at any heteroatom or carbon atom whichresults in a stable structure. The heterocyclic rings described hereinmay be substituted on carbon or on a nitrogen atom if the resultingcompound is stable. If specifically noted, a nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, xanthenyl. Preferred 5 to 10 membered heterocyclesinclude, but are not limited to, pyridinyl, pyrimidinyl, triazinyl,furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl,benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl,benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl,and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, butare not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl,thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 6 memberedheterocycles include, but are not limited to, pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl,pyrazolyl, imidazolyl, and tetrazolyl. Also included are fused ring andspiro compounds containing, for example, the above heterocycles.

As used herein, the term “aryl”, “C₆-C₁₀ aryl” or aromatic residue, isintended to mean an aromatic moiety containing the specified number ofcarbon atoms; for example phenyl, pyridinyl or naphthyl. Unlessotherwise specified, “aryl” may be unsubstituted or substituted with 0to 3 groups selected from H, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂,N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃,CH₂CH₃, CO₂H, and CO₂CH₃.

The phrase “additional lactam carbons and thiolactam carbons”, as usedherein, is intended to denote the number of optional carbon atoms in thelactam ring or thiolactam ring B of Formula (I). Formula (I″):

represents the lactam ring B of Formula (I). The ring numbering shownfor lactams of Formula (I″) applies to analogous thiolactams. Additionallactam carbons are carbons in lactam ring B other than the carbonsnumbered 2 and 3 in the backbone of the formula. The additional lactamcarbons may be optionally replaced by a heteroatom selected from oxygen,nitrogen and sulfur. Lactam ring B contains 1, 2, 3, 4, 5, 6 or 7optional carbons, wherein one optional carbon may optionally be replacedby a heteroatom, such that the total number of members of lactam ring B,including atoms numbered 1, 2 and 3 in the backbone, does not exceed 10.It is preferred that the total number of atoms of lactam ring B is 6, 7or 8; it is more preferred that the total number of atoms of lactam ringB is seven. Examples of lactam ring B include:

and their thiolactam counterparts. The examples are not intended tolimit the invention. Preferred examples of lactam ring B are B1, B2, B5,B6, B8, B9, B13, and B16; more preferred examples of lactam ring B areB1, B6, B8, B9, and B13. Preferred examples of substituent R¹⁰ or R¹¹ onlactam B are methyl, ethyl, phenyl, 4-fluorophenyl, 4-chlorophenyl,4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, and(4-trifluorophenyl)methyl.

The compounds herein described may have asymmetric centers. Oneenantiomer of a compound of Formula (I) may display superior chemicalactivity over the opposite enantiomer. For example carbon 3 of lactamring B Formula (I″) may exist in either an S or R configuration. Thus,an R or S configuration at carbon 3 in Formula (I″) is considered partof the invention. An example of such configuration includes,

but is not intended to be limited to this example of ring B. Whenrequired, separation of the racemic material can be achieved by methodsknown in the art. Additionally, the carbon atoms to which R³ and R⁵ areattached may describe chiral carbons which may display superior chemicalactivity over the opposite enantiomer. For example, where R³ and R⁵ arenot H, then the configuration of the two centers may be described as(2R,3R), (2R,3S), (2S,3R), or (2S,3S). All configurations are consideredpart of the invention; however, the (2R,3S) and the (2S,3R) arepreferred and the (2R,3S) is more preferred.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

“Prodrugs” are intended to include any covalently bonded carriers whichrelease the active parent drug according to formula (I) in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of acompound of formula (I) are prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include compounds of formula (I) wherein a hydroxy,amino, or sulfhydryl group is bonded to any group that, when the prodrugor compound of formula (I) is administered to a mammalian subject,cleaves to form a free hydroxyl, free amino, or free sulfhydryl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of formula (I), and the like.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents which are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

Methods for the synthesis of succinylamino lactams are known in the artand are disclosed in a number of references including PCT publicationnumber WO 96/29313, which is hereby incorporated by reference.

Disubstituted succinate derivatives can be prepared by a number of knownprocedures. The procedure of Evans (D. A. Evans et al, Org. Synth. 86,p83 (1990)) is outlined in Scheme 1 where acylation of an oxazolidinonewith an acylating agent such as an acid chloride provides structures 1.Alkylation to form 2 followed by cleavage of the chiral auxiliary andsubsequent alkylation of the dianion of the carboxylic acid 3 provides avariety of disubstituted succinates which can be separated andincorporated into structures of Formula (I) by those skilled in the art.Additional examples are found in P. Becket, M. J. Crimmin, M. H. Davis,Z. Spavold, Synlett, (1993), 137-138, incorporated herein by reference.

Diastereomerically pure succinate derivatives can be accessed using thechemistry outlined below, adapted from P. Becket, M. J. Crimmin, M. H.Davis, Z. Spavold, Synlett, (1993), 137-138 incorporated herein byreference. This reference provides the synthesis below to obtaincompound 9. Compound 11 is used as an intermediate and is prepared from9 by hydrogenation of the allyl group followed by coupling of9-fluorenemethanol under standard conditions using DCC and DMAP inCH₂Cl₂. Deprotection of the tert-butyl ester is accomplished bytreatment with 50% trifluoroacetic acid.

Additional methods useful for the preparation of succinate derivativesare known by those skilled in the art. Such references include, McClureand Axt, Bioorganic & Medicinal Chemistry Letters, 8 (1998) 143-146;Jacobson and Reddy, Tetrahedron Letters, Vol 37, No. 46, 8263-8266(1996); Pratt et al., SYNLETT, May 1998, p. 531; WO 97/18207; and WO98/51665. The synthetic disclosures of WO97/18207 and WO 98/51665 arehereby incorporated by reference.

A variety of compounds of Formula (I) can be prepared by methodsdescribed in Scheme 4. The protected α-amine 3 of theα-amino-ε-caprolactam can be prepared by methods well known in theliterature for amino protecting groups as discussed in Theodora W.Greene's book “Protective Groups in Organic Synthesis”, like N-Boc usingdi-t-butyldicarbonate in an appropriate solvent like DMSO. A sulfur atomcan be introduced into the ring providing L-α-amino-β-thio-ε-caprolactamaccording to the procedure in S. A. Ahmed et al, FEBS Letters, (1984),vol. 174, pages 76-9 (Scheme 3). One skilled in the art can extend thismethodology to the synthesis of β-amino and oxygen containing rings byanalogy. The sulfur-containing molecules can also be oxidized to thesulfoxide and sulfone by methods known to one skilled in the art.

The lactam nitrogen of compound 13 can be alkylated by generating theanion with bases such as LDA, lithium bis(trimethylsilyl)amide or sodiumhydride in solvents like THF, with or without cosolvents such as DMPU orHMPA and reacting this with a variety of groups containing leavinggroups (X″) like bromide, iodide, mesylate or tosylate. Alkylatingagents such as α-bromo amides, ketones and acids can be prepared by anumber of literature methods including halogenation of amino acids bydiazotization or are commercially available. Other suitable alkylatingagents such as alkyl, allylic and benzylic halides can be formed form avariety of precursors such as free-radical addition of halides oractivation of alcohols, and other chemistries known to those skilled inthe art. For discussion of these types of reactions, see Carey, F. A.and Sundberg, R. J., Advanced Organic Chemistry, Part A, New York:Plenum Press, 1990, pages 304-305, 342-347, 695-698.

The N-Boc protecting group can be removed by any number of methods wellknown in the literature like TFA in methylene chloride to give thecompound 15. The amine 15 can be coupled to an appropriately substitutedcarboxylic acid or acid chloride by methods well described in theliterature for making amide bonds, like TBTU in DMF with a base like NMMto give the elaborated compound 16. Compounds 16 can be alkylated usingstandard bases like LDA, NaH, or NaHMDS to deprotonate the amidefollowed by addition of an alkylating agent with an appropriate leavinggroup like halide, mesylate, or triflate in an appropriate solvent toprovide compounds 17 with an R⁶ substituent. The t-butyl ester is thenremoved by treatment with TFA in methylene chloride to give thecarboxylic acid 17.

The final compounds 18 were prepared by treating the activatedcarboxylic acid of 17 with an appropriately substituted amine. Forinstance, activation of the carboxylic acid with HATU(O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluroniumhexafluorophosphate) or PyBOP(benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate) or other coupling agents known to those skilled inthe art allows condensation with ammonia to form primary amides.Similarly, condensation of the activated acid with hydroxylaminehydrochloride provides the hydroxamic acid, or reaction with a primaryor secondary amine provides the substituted amine derivative.

Activation of the acid with PyBrOP (bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate) followed by addition of an alcohol and4-dimethylaminopyridine allows formation of the ester directly. Foradditional acylation reactions see for example Carey, F. A. andSundberg, R. J., Advanced Organic Chemistry, Part A, New York: PlenumPress, 1990, pages 475-479.

Additional Examples of compounds of Formula (I) can be prepared as shownin Scheme 5. A suitable resin for solid phase synthesis such as Fmoc(Fluorenylmethylcarbonyl)-protected hydroxylamine bound to polystyrenebeads can be purchased from Novabiochem, Inc. Deprotection of the Fmocgroup under standard conditions using 20% piperidine in DMF providestrityl-linked hydroxylamine resin. Coupling of afluorenylmethyl-protected succinic acid derivative such as 20 with acoupling agent such as HATU in a suitable solvent like DMF orN-methylpyrrolidinone provides the support-bound hydroxamate 21. TheFluorenylmethyl ester can be removed using 20% piperidine in DMF toprovide the free carboxylic acid which can be coupled to amines like thecaprolactam 22 (which is available using chemistry outlined in Scheme 4)using PyBOP.(benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate) and a suitable base like DIEA in DMF or NMP. Thesupport-bound intermediate 23 can then be elaborated to biarylstructures of the type 24 using typical Suzuki coupling conditionsemploying a catalyst such as Palladium complexes liketetrakis(triphenylphosphine)-palladium with 2M aqueous sodium carbonateas a base in a suitable solvent like THF or DME and an excess of aboronic acid. The final compounds are liberated from the supportemploying dilute (5%) trifluoroacetic acid in CH₂CL₂ and purified byconventional chromatography.

General Procedure for Solid-Phase Synthesis according to Scheme 5.

Resin 20 of Scheme 5: Fmoc-protected resin 19 (2.0 g, 0.78 mmol/g, 1.56mmol) is purchased from Novabiochem and swelled in 20 ml of CH₂Cl₂ for 1hour. The CH₂Cl₂ is removed and the resin is then treated with 25% v/vpiperidine in DMF (8 mL) and allowed to shake slowly for 16 h. Thesolvent was removed by filtration and the resin was shaken with anadditional 8 mL of 25% v/v piperidine in DMF for 2 h at rt. The solventswere removed by filtration, and the resin 20 was rinsed 3× with 20 mL ofDMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH₂Cl₂ and dried invacuo.

Succinate 10 of Scheme 2: Succinate 9 is prepared according to theliterature procedure (P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold,Synlett, (1993), 137-138). Succinate 9 (17.8 g, 66 mmol) is dissolved in250 mL of ethyl acetate and placed in a Parr shaker bottle. To thesolution is added 890 mg of 5% palladium on carbon, and the bottle ispressurized to 40 psi with hydrogen gas and shaken for 2.5 h at rt. Thehydrogen is removed and the palladium catalyst is removed by filtrationthrough a pad of celite. Concentration of the ethyl acetate solutionprovides 17.5 g (98%) of succinate 10. No further purification isnecessary. MS (M−H)⁺=271.

Succinate 21 of Scheme 5: Succinate 10 (6.3 g, 23.1 mmol) is dissolvedin 125 mL of CH₂Cl₂ and 4.8 g (23.3 mmol) of dicyclohexylcarbodiimide isadded. The solution is stirred at rt for 30 min and then 4.6 g (23.4mmol) of 9-fluorenemethanol is added followed by 122 mg (1 mmol) of4-dimethylaminopyridine. After 5 h of stirring at rt, the reactionsolution was diluted with an additional 100 mL of CH₂Cl₂ and filteredthrough a pad of celite to remove precipitated dicyclohexylurea. Thesolution was then washed 3× with 50 mL of a 1N HCl solution, 3× with 50mL of a saturated sodium bicarbonate solution, and 2× with 50 mL ofbrine. The crude product was dried over MgSO₄ and concentrated onto 15 gof silica gel. Chromatography eluting with a gradient of 2.5% to 5%ethyl acetate/hexanes provided 6.4 g (61%) of the diester as an oil. Thepurified diester (6.4 g 14.2 mmol) is then dissolved in 25 mL of CH₂Cl₂,25 mL of trifluoroacetic acid is added, and the reaction solution isstirred at rt for 2 h. The reaction solution is directly concentrated invacuo to an oil which is then redissolved in 25 mL of toluene andreconcentrated, followed by drying in vacuo to provide 6.3 g (98%) ofthe desired succinate 9 as an oil which solidifies on standing. MS(M+Na)⁺=471, (M+2Na)⁺=439.

Caprolactam 23 of Scheme 5: Boc-caprolactam 14 (5.0 g 21.9 mmol) isdissolved in 60 mL of THF and chilled to −78° C. To the chilled solutionis added 24 mL of a 1.0 M solution of lithium bis(trimethylsilyl)amidein THF, and the solution was brought to 0° C. and stirred for 15 min. Tothe anion solution was added 6.5 g (22 mmol) of 3-iodobenzyl bromide(Aldrich) and the solution was allowed to warm to rt and stirred for 18h. The reaction solution was diluted with 50 mL of water and extracted3× with ethyl acetate. The combined organic layers were dried over MgSO₄and concentrated in vacuo. The crude product was purified bychromatography eluting with a gradient of 5-20% ethyl acetate/hexanes toafford 7.0 g (72%) of the title compound as a white solid. MS(M+Na)⁺=467.

Resin 22 of Scheme 5: Resin 22 (2.0 g, 0.78 mmol/g, 1.56 mmol) wasswollen in 3 mL of DMF. In a separate flask, 1.85 g (4.68 mmol) ofsuccinate 21 was dissolved in 3 mL of DMF and 2.5 mL ofN,N-diisopropylethylamine (14 mmol) was added, followed by 1.81 g (4.68mmol) of HATU. The solution containing the active ester was added to theslurried resin and the reaction suspension was slowly shaken for 18 h.The resin was then washed 3× with 20 mL of DMF, 3× with 20 mL ofmethanol, and 3× with 20 mL of CH₂Cl₂. Loading of the resin wasdetermined by Fmoc quantitation to be 0.25 mmol/g, see Reddy, M. P.;Voelker, P. J. Int. J. Pept. Protein Res. 1998, 31, 345-348.

Resin 24 of Scheme 5: Resin 22 (2.0 g , 0.25 mmol/g, 0.5 mmol) wassuspended in 10 mL of 25% piperidine in DMF. The suspended resin wasshaken for 30 min at rt, and then the resin was washed 3× with 20 mL ofDMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH₂Cl₂. Deprotectedresin (1.0 g, 0.25 mmol) was swollen in 2 mL of DMF. To the slurry wasadded 650 mg (1.25 mmol) of PyBOP and 217 mL (1.25 mmol) of DIEA.Separately, 443 mg (0.97 mmol) of caprolactam 23 was dissolved in 2 mLof DMF and 436 mL (2.5 mmol) of DIEA was added. The caprolactam solutionwas added to the resin slurry and the resin was mixed for 18 h at rt.The solvents were then removed and the coupling was repeated, withshaking at rt for 6 h. The resin was then washed 3× with 10 mL of DMF,3× with 10 mL of methanol, and 3× with 10 mL of CH₂Cl₂.

Products 25 of Scheme 5: A 70 mg (17.5 mmol) portion of resin 24 wassuspended in 1 mL of THF in a screw-cap vial. To the slurry was added aboronic acid (0.15 mmol), 150 mL of a 2 M solution of sodium carbonate,and 15 mg (13 mmol) of tetrakis(triphenylphosphine)palladium. The vialwas tightly closed and heated to 60° C. for 16 h using a dry heater on ashaker table. The solvents were then removed by filtration and the resinwas washed 3× with THF (2 mL), 3× with methanol (2 mL), 3× with water,and 3× with CH₂Cl₂. The resins were then placed in a glass vial andcleaved with 1 mL of 5% trifluoroacetic acid in CH₂Cl₂ for 30 min. Thesolution ws filtered off and the resin was washed with an additional 2mL of CH₂Cl₂ and the combined filtrates were evaporated to dryness toyield the crude products 25. The products were purified bychromatography eluting with 10-100% ethyl acetate in hexanes to yield13.0 to 6.0 mg (14-60%) of the final products.

Additional Examples of compounds of Formula (I) can be prepared as shownin Scheme 6. A suitable resin for solid phase synthesis such as Fmoc(Fluorenylmethylcarbonyl)-protected peptide amide linker(PAL)-derivatized polystyrene beads can be purchased from Perkin ElmerBiosystems, Inc. Deprotection of the Fmoc group under standardconditions using 20% piperidine in DMF provides the free benzylamine.Coupling of a succinic acid derivative such as 28 (which is availableusing chemistry outlined in Scheme 4) with a coupling agent such as HATUin a suitable solvent like DMF or N-methylpyrrolidinone provides thesupport-bound amide 29. The support-bound intermediate 29 can then beelaborated to biaryl structures of the type 24 using typical Suzukicoupling conditions employing a catalyst such as Palladium complexeslike tetrakis(triphenylphosphine)-palladium with 2M aqueous sodiumcarbonate as a base in a suitable solvent like THF or DME and an excessof a boronic acid. The final compounds are liberated from the supportemploying 50% trifluoroacetic acid in CH₂Cl₂ and can be purified byconventional chromatography or preparative HPLC.

General Procedure for Solid-Phase Synthesis According to Scheme 6

Resin 27 of Scheme 6: Fmoc-protected PAL resin 26 (0.80 g, 0.50 mmol/g,0.40 mmol) is purchased from Advanced Chemtech and swelled in 20 ml ofCH₂Cl₂ for 1 hour. The CH₂Cl₂ is removed and the resin is then treatedwith 25% v/v piperidine in DMF (6 mL) and allowed to shake slowly for 1h. The solvents were removed by filtration, and the resin 27 was rinsed3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL ofCH₂Cl₂. and dried in vacuo.

Acid 28 of Scheme 6: To a solution of 0.100 g (367 mmol) of succinate 10dissolved in 2.0 mL of dry DMF was added 0.120 mL (1.10 mmol) ofN-methylmorpholine. A second solution containing 0.139 g (0.403 mmol) ofcaprolactam 23 of Scheme 5 dissolved in 2.0 mL of DMF was then added. Tothe mixed solution was added 229 mg (0.440 mmol) of PyBop and thereaction solution was stirred for 16 h at rt. The reaction solution wasdiluted with water (20 mL) and extracted 3× with 100 mL of ethylacetate. The combined organic layers were dried with Na₂SO₄ andconcentrated under reduced pressure. The resulting oil was purified bychromatography eluting with a gradient of 5-20% ethyl acetate in hexanesto provide 0.195 g (0.360 mmol, 98%) of the tert-butyl ester of Acid 28(MS M+Na=621). The purified ester (0.195 g, 0.360 mmol) was dissolved in10 mL of 25% trifluoroacetic acid in CH₂Cl₂ and stirred for 2 h at rt.The solvents were removed under reduced pressure and the acid wasredissolved in 5 mL of toluene and reconcentrated 2× to remove residualTFA. The crude acid was found to be pure by ¹H NMR and was used inScheme 6 without further purification.

Resin 29 of Scheme 6. Resin 27 (800 mg, 0.40 mmol) was solvated in 4.0mL of dry DMF and 0.63 mL (3.6 mmol) of diisopropylethylamine was addedfollowed by a solution of Acid 28 dissolved in 4 mL of DMF. To theslurry was then added 0.465 g (1.2 mmol) of HATU and the slurry wasshaken for 26 h at rt. The solvents were removed by filtration, and theresin 29 was rinsed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and3× with 20 mL of CH₂Cl₂. and dried in vacuo.

Products 30 of Scheme 6: A 75 mg (0.38 mmol/g, 28.8 mmol) portion ofresin 24 was suspended in 1 mL of THF in a screw-cap vial. To the slurrywas added a boronic acid (0.33 mmol), 150 mL of a 2 M solution of sodiumcarbonate, and 15 mg (13 mmol) of tetrakis(triphenylphosphine)palladium.The vial was tightly closed and heated to 60° C. for 16 h using a dryheater on a shaker table. The solvents were then removed by filtrationand the resin was washed 3× with THF (2 mL), 3× with methanol (2 mL), 3×with water, and 3× with CH₂Cl₂. The resins were then placed in a glassvial and cleaved with 1 mL of 5% trifluoroacetic acid in CH₂Cl₂ for 2 h.The solution was filtered off and the resin was washed with anadditional 2 mL of CH₂Cl₂ and the combined filtrates were evaporated todryness to yield the crude products 25. The products were purified bychromatography eluting with 10-100% ethyl acetate in hexanes to yield0.5 to 2.0 mg (14-60%) of the final products.

The internal phenyl ring can be exchanged for a pyridine ring usingchemistry outlined in Scheme 7. The chloromethyl pyidine 33 is preparedusing a known procedure reported in Nutaitis, Charles F.; Ledeboer, MarkW. Org. Prep. Proced. Int. (1992), 24(2), 143-6 Incorporated herein byreference. After freebasing the pyridine, alkylation with theBoc-caprolactam provides pyridine intermediate 34, which can beelaborated to the protected amide 35 with succinate 10. Substitution canthen be introduced using Suzuki methodology employing a palladium sourcesuch as tetrakis(triphenylphosphine) palladium(0) orbis(diphenylphosphinoferrocene) palladium(II) dichloride and a suitablebase such as sodium carbonate or triethylamine in a solvent such as THFor toluene containing 10% methanol. Stille chemistry is also possibleusing a suitable palladium source such astetrakis(triphenylphosphine)palladium(0) and an aryl or vinyl tinderivative in a solvent such as benzene, toluene, or xylenes. Thetert-butyl ester is then deprotected under standard acidic conditionsusing trifluoroacetic acid and the amide is formed under standardconditions to provide products 36.

General Procedure for Synthesis According to Scheme 7

The chloromethyl pyidine HCl salt 33 is prepared using a known procedurereported in Nutaitis, Charles F.; Ledeboer, Mark W. Org. Prep. Proced.Int. (1992), 24(2), 143-6.

Caprolactam 34: Pyridine HCl salt 33 (2.0 g, 8.3 mmol) is dissolved in50 mL of a saturated NaHCO₃ solution and the solution is extracted with30 mL of CH₂Cl₂ 3× followed by concentration of the organic layers toprovide the free base. Separately, 1.8 g (7.8 mmol) of caprolactam 13 isdissolved in 40 mL of dry THF and chilled to −78° C. To the solution wasadded 8.7 mL of a 1M solution of sodium bis(trimethylsilyl) amide. Thesolution was brought to 0° C. and stirred for 30 min. To the resultantanion was added a solution of 1.7 g (8.3 mmol) of pyridine 33 free basedissolved in 40 mL of THF. The resulting reaction solution was stirredat rt for 18 h and then heated to 50° C. and stirred an additional 3 h.The reaction solution was allowed to cool and then 50 mL of water wasadded and the aqueous layer was extracted 2× with 100 mL of ethylacteate. The combined organic layers were dried and concentrated underreduced pressure to provide the crude product which was purified bychromatography eluting with 20 to 100% ethyl acetate in hexanes toprovide 1.5 g (51%) of caprolactam 34 as an oil.

Amide 35: Caprolactam 34 (0.40 g, 1.0 mmol) is dissolved in 20 mL of 50%trifluoroacetic acid in CH₂Cl₂ and stirred at rt for 30 min. Thesolvents were then removed under reduced pressure and the resulting oilwas redissolved in 5 mL of toluene and reconcentrated to remove residualTFA. Separately, 0.270 g (1.0 mmol) of succinate 10 was dissolved in 5.0mL of dry DMF and 0.44 mL (4 mmol) of N-methylmorpholine was addedfollowed by 0.50 g (1.3 mmol) of HATU and the resulting solution wasstirred at rt for 30 min. The crude deprotected caprolactam from abovewas dissolved in 5.0 mL of dry DMF and added to the succinate solutionand the resulting solution was heated to 50° C. and stirred for 2 days.The solution was then diluted with 20 mL of water and extracted with 350 mL portions of ethyl acetate. The combined organic layers were driedand concentrated under reduced pressure to provide an oil which waspurified by chromatography eluting with 20 to 50% ethyl acetate inhexanes to provide 0.40 g (70%) of the Amide 35.

Additional examples can be prepared by the method shown in Scheme 8.Coupling of an amine onto a commercially available aldehyde-derivedresin 37 under conditions for reductive amination such as sodiumtris(acetoxy)borohydride in CH₂Cl₂ containing 1% acetic provides asupport-bound amine 38. The carboxylic acid 39 can then be coupled tothe support-bound amine generating an amide 40 which can be liberatedfrom the support employing trifluoroacetic acid in CH₂Cl₂.

General Procedure for Solid-phase Synthesis According to Scheme 8

Resin 38 of Scheme 5: Aldehyde-derived resin 37 (200 mg, 0.5 mmol/g, 0.1mmol) is purchased from Perkin Elmer Biosystems and swelled in 3 ml ofCH₂Cl₂ for 1 hour. An amine (1.0 mmol), sodium tris(acetoxy)borohydride(106 mg, 0.5 mmol) and acetic acid (30 uL, 1%) are added and thereaction is shaken on a shaker table for 16 h at rt. The solvents wereremoved by filtration and the resin 38 was rinsed 3× with 20 mL of DMF,3× with 20 mL of methanol, and 3× with 20 mL of CH₂Cl₂. and dried invacuo.

Products 40 of Scheme 8: Carboxylic acid 39 (23 mg, 0.045 mmol),diisopropylethylamine (13 mL, 0.075 mmol) and HATU (17.1 mg, 0.045 mmol)were mixed in 0.5 mL of DMF for 30 min. Amine-derived resins 38 (30 mg,0.015 mmol) were then added and the suspension was shaken at rt for 16h. The solvents were removed by filtration and the resins were rinsed 3×with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL ofCH₂Cl₂. The isolated resins were then cleaved by the addition of 0.50 mLof trifluoroacetic acid. The product solutions were concentrated andredissolved in 0.5 mL of methanol and reconcentrated 2× to removeresidual TFA. Product yields ranged from 0-100% based on the structureof the amine.

The compounds of Formula (I) of the present invention can also beprepared from aminolactam or aminothiolactam 42 and succinic acidderivatives 41 using amide bond syntheses known in the art, includingmethods commonly used in peptide syntheses, such as HATU, TBTU, BOP,pyBOP, EDC, CDI, DCC, hydroxysuccinimide, mixed carboxylic anhydride,and phenyl ester mediated couplings, as illustrated in Scheme 9 for thesynthesis of aminolactam or aminothiolactam 43, an embodiment of thepresent invention.

Depending on the structure of the final product, it is appreciated bythose skilled in the art that protecting groups or precursorfunctionality convertable to the desired groups may be desireable.Protecting groups and their use in synthesis are described in Green andWuts, Protective Groups in Organic Synthesis, (Wiley 1991). The use ofprotecting groups is further illustrated in Scheme 10, in which thesuccinate half-ester 44 (Becket et al., Synlett 1993, 137-138) iscoupled to the aminobenzodiazepine 45 (Sherrill and Sugg, J. Org. Chem.1995, 60, 730-734; Bock et al., J. Med. Chem., 1993, 36, 4276-4292) togive ester 46, followed by conversion of the ester group to the primaryamide 47.

Methods for the synthesis of lactams as contemplated by the presentinvention in lactam ring B in Formula (I), including aminobenzodiazepines, are known in the art and are disclosed in a number ofreferences including PCT publication number WO 98/28268, which is herebyincorporated by reference. Additional references include Bock, et al, J.Org. Chem., 1987, 52, 3232-3239 and Sherrill et al, J. Org. Chem., 1995,60, 730-734; Walsh, D. A., Synthesis, September 1980, p.677.

The synthesis of the thiolactams of the present invention (Formula (I),A=S) can be carried out using thiolactam intermediates (42, A=S), usingthe methods described above. The thiolactam intermediates may beprepared from suitably protected aminolactams employing methods known tothose skilled in the art, using, for example, Lawesson's reagent, P4S10,or related methods (see Taylor et al., Bioorg. Med. Chem. Lett. 1997, 7(4), 453-456; Schwarz et al., Tetrahedron, 1997, 53 (26), 8795-8806;Achour et al., Synth. Commun. 1994, 24 (20), 2899-2905; Buege et al.,Arch. Pharm. 1994, 327 (2), 99-103; Levai, et al., Arch. Pharm. 1992(325 (11), 721-726; Duhammel et al., Tetrahedron Asymmetry 1991, 2 (3),203-206; Bodine et al., Synth. Commun. 1982, 12, 787). Deprotection ofthe amine, coupling to an appropriate succinate derivative andelaboration of the distal succinic acid derivative provides the desiredthiolactams of the present invention.

EXAMPLES

Chemical abbreviations used in the Examples are defined as follows:“DMPU” for 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, “TBTU” forO-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate,and “BOP” for benzotriazol-1-yloxytris-(dimethylamino)phosphoniumhexafluorophosphate. It is understood that one skilled in the art candiscern compounds used in the synthesis of Examples of the invention maybe referred to by structure and number. For example, Resin 20 refers tothe resin of structure 20 in Scheme 5; succinate 9 refers to thestructure 9 found in Scheme 2 which is a succinate compound.

“HPLC” is an abbreviation used herein for high pressure liquidchromatography. Reverse-phase HPLC was carried out using a Vydac C-18column with gradient elution from 10% to 100% buffer B in buffer A(buffer A: water containing 0.1% trifluoroacetic acid, buffer B: 10%water, 90% acetonitrile containing 0.1% trifluoroacetic acid).

Example 1 (2R,3S)N1-[(3S)-hexahydro-1-(3,3-diphenylpropyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Step (1a): Di-tert-butyldicarbonate (10.2 g, 46.7 mmoles) was addedportion wise to a solution of L-(−)-α-amino-ε-caprolactam (5.0 g, 39.0mmoles) in dimethyl sulfoxide (30 mL). After 5 h at rt, the reaction waspartitioned between water (100 mL) and ethyl acetate. The combinedorganic extracts were washed successively with 1 M HCl (50 mL), brine,and dried (MgSO₄) and concentrated in vacuo. The residue wasrecrystallized in 1:1 v/v ether-hexanes, two crops yielded the desiredproduct (6.26 g, 70%) as white solid. MS (M+H-BOC)⁺=129.Step (1b): Triphenylphosphine (3.0 g, 11.4 mmoles) and carbontetrabromide (3.75 g, 11.7 mmoles) were added successively to a cooled(0° C.) solution of 3,3-biphenyl-1-propanol (1.5 mL, 7.5 mmoles) indichloromethane (20 mL). After 1.5 hours at rt, the mixture wasconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel (hexanes) to give the desired product (1.93 g, 93% yield)as a clear oil. MS (M-BrC₂H₄)⁺=167Step (1c): A 1.0 M tetrahydrofuran solution of lithiumbis(trimethylsilyl)amide (1.3 mL) was added over 15 minutes to compoundof Step (1a) (0.29 g, 1.27 mmoles) in tetrahydrofuran (3 mL) and DMPU (2mL) at −78° C. The iodo compound prepared from compound (1b) (0.85 g,3.09 mmoles) by typical Finkelstein methodology, in tetrahydrofuran (4mL) was added and the reaction was allowed to warm to rt slowly. Thiswas stirred for 10 hours at ambient temperature, partitioned betweenwater and ethyl acetate. The combined organic extracts were washedsuccessively with water (20 mL), brine (20 mL), and dried (MgSO₄) andconcentrated in vacuo. The resulting residue was purified by silica gelcolumn (ethyl acetate:hexanes, 5:95 then ethyl acetate:hexanes, 15:85)to give the desired product (0.16 g, 30%). MS (M-Ot-Bu)⁺=349.Step (1d): Trifluoroacetic acid (3 mL) was added to a solution ofcompound of Step (1c) (0.16 mg, 0.38 mmoles) in dichloromethane (9 mL).After 2 h at rt, the solvent was removed in vacuo. The residualtrifluoroacetic acid was removed by azeotrope with dichloromethane (50mL), toluene (50 mL), and dichloromethane (50 mL) successively to givethe desired product (0.17 g, 99%) as a yellow oil. MS (M+H)⁺=323.Step (1e): 4-Methylmorpholine (0.6 mL, 5.46 mmoles) and TBTU (0.11 g,0.34 mmoles) were added to a solution of succinate acid (P. Becket, M.J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138) (0.085 g,0.31 mmoles) in N,N-dimethylformamide (3 mL). After 30 minutes at rt,the compound from step (1d) (0.17 g, 0.39 mmoles) was added to themixture. The reaction was stirred for 16 h at rt, then partitionedbetween 1 M HCl (20 mL) and ethyl acetate. The combined organic extractswere washed successively with saturated aqueous sodium bicarbonate (20mL), water (20 mL), brine (20 mL), dried (MgSO₄) and concentrated invacuo. The residue was purified by silica gel chromatography (ethylacetate:hexanes, 7:93 gradient to ethyl acetate:hexanes 25:75) to givethe desired product (120 mg, 67%) as a clear oil. MS (M+NH₄-Ot-Bu)⁺=521.Step (1f): Trifluoroacetic acid (3 mL) was added to a solution ofcompound of Step (1e) (120 mg, 0.21 mmoles) in dichloromethane (9 mL).After 3 hours at rt, the mixture was concentrated in vacuo. The residualtrifluoroacetic acid was removed by azeotrope with toluene (1×50 mL) anddichloromethane (1×50 mL). The residue was triturated with Et2O:Hexanes95:5, to give the desired product (75 mg, 70%) as a white solid. MS(M−H)⁻=519.Step (1g): 4-Methylmorpholine (0.05 mL, 0.45 mmoles) and BOP (73 mg,0.17 mmoles) were added to a solution of compound of Step (1f) (60 mg,0.12 mmoles) in N,N-dimethylformamide (2 mL). Hydroxylamine (33 mg, 0.47mmoles) was added to the mixture, the reaction was stirred for 16 h atrt, was concentrated in vacuo, was acidified with trifluoroacetic acid,then purified by reverse phase HPLC on a Vydac C-18 column, to give thedesired hydroxamic acid as a white solid (45 mg, 75%). MS (M−H)⁻=534.

Example 2 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Step (2a): Triphenylphosphine (3.40 g, 13.0 mmoles) andcarbontetrabromide (4.20 g, 13.0 mmoles) were added successively to asolution of m-phenoxybenzyl alcohol (1.5 mL, 8.6 mmoles). After 4 h atrt the mixture was concentrated and was purified by silica gel column(hexanes, then ethyl acetate:hexanes, 5:95) to give the desired bromide(1.3 g, 57%) as a yellow oil. MS (M−Br)⁺=183.Step (2b): A 1 M solution of lithium bis(trimethylsilyl)amide was addeddropwise to a solution of compound of Step (1a) (0.3 g, 1.31 mmoles) intetrahydrofuran (5 mL) at −78° C. After 30 minutes a solution ofcompound of Step (2a) (0.43 g, 1.63 mmoles) in tetrahydrofuran (4 mL)was added to the mixture dropwise. The reaction was allowed to come toambient temperature, stirred for 16 h, then partitioned between waterand ethyl acetate. The combined organic extracts were washedsuccessively with water (20 mL), brine (20 mL), dried (MgSO₄) andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (ethyl acetate:hexanes, 5:95 then ethyl acetate:hexanes,15:85) to give the desired product (360 mg, 67%) as a clear oil. MS(M-Ot-Bu)⁺=337.Step (2c): Trifluoroacetic acid (5 mL) was added to a solution ofcompound of Step (2b) in dichloromethane (15 mL). After 3 h at rt thesolution was concentrated in vacuo. The residual trifluoroacetic acidwas removed from residue by azeotrope with toluene (50 mL) thendichloromethane (30 mL) to yield the desired amine (390 mg, 99%) as aclear oil. MS (M+H)⁺=311.Step (2d): Following a procedure analogous to the preparation of Step(1e), but using the compound from of Step (2c) (390 mg, 0.88 mmoles) theamide was prepared, The crude compound was purified by silica gelchromatography to give the desired product (0.38 g, 92%) as a yellowoil. MS (M-Ot-Bu)⁺=491.Step (2e): Following a procedure analogous to the preparation of step(1f), but using the compound from Step (2d) (380 mg, 0.67 mmoles), thecarboxylic acid was prepared. The product was precipitated from ethylether with hexanes, to give the desired acid (227 mg, 66%) as a whitesolid. MS (M−H)⁻=507.Step (2f): Following a procedure analogous to the preparation ofcompound of Step (1g), but using the compound from step (2e) (150 mg,0.29 mmoles) the title compound was prepared. The crude was purified byreverse phase HPLC on a Vydac C-18 column to give the desired product(90 mg, 58%) as a white solid. MS (M−H)⁻=522.

Example 3 (2R,3S)N1-[(3S)-hexahydro-1-(phenyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Step (3a): Triethylamine (1.5 mL, 10.8 mmoles), copper (II) acetate(0.95 g, 5.2 mmoles) and phenylboric acid (1.6 g, 13.1 mmoles) wereadded successively to a solution of compound of Step (1a) (1.0 g, 4.4mmoles) in dichloromethane (20 mL). After 2.5 h at rt, more phenylboricacid (0.5 g, 4.1 mmoles) was added to the mixture. After an additional 3hours at rt more phenylboric acid (0.5 g, 4.1 mmoles) was added to themixture. After 65 h at rt, the mixture was filtered over celite. Thefiltrate was concentrated in vacuo, and the residue was purified bysilica gel chromatography (ethyl acetate:hexanes, 5:95 then 15:85) togive the desired product (250 mg, 19%). MS (M-Ot-Bu)⁺=231.Step (3b): Following a procedure analogous to the preparation ofcompound of Step (2c), but using compound of Step (3a) (250 mg, 0.82mmoles), the amine (300 mg, 99%) was prepared as a yellow oil. MS(M+H)⁺=205.Step (3c): Following a procedure analogous to the preparation ofcompound of Step (1e), but using compound from Step (3b) (0.3 g, 0.94mmoles), the amide was prepared. The residue was purified by silica gelchromatography (ethyl acetate:hexanes, 5:95 to 20:80 in 5% increments,500 mL each ratio) to give the desired product (210 mg, 60%) as a clearoil. MS (M+H-t-Bu)+=403.Step (3d): Following a procedure analogous to the preparation ofcompound of Step (1f), but using compound from sStep (3c) (200 mg, 0.44mmoles) the acid was prepared. The crude oil was triturated withether:hexanes 1:1 to give the desired acid (114 mg, 65%) as a whitesolid. MS (M−OH)⁺=385.Step (3e): Following a procedure analogous to the preparation ofcompound of Step (1g), but using compound from Step (3d) (82 mg, 0.20mmoles) the title compound was prepared. The crude product was purifiedby reverse phase HPLC on a Vydac C-18 column to give the desired product(80 mg, 94%). MS (M−H)⁻=416.

Example 4 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(methyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Following a procedure analogous to the preparation of Example 3,compound of Step (2e) (100 mg, 0.20 mmol) was treated with HATU(O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluroniumhexafluorophosphate) (114 mg, 0.30 mmol) and N-methyl morpholine (66 mL,0.6 mmol) in 2 mL of DMF for 15 min at rt. A solution of 2.0 Mmethylamine in THF (0.2 mL, 0.4 mmol) was added and the reactionsolution was stirred for 1 h at rt. The reaction solution was dilutedwith 1N HCl (5 mL) and extracted 3× with 10 mL of ethyl acetate. Thecombined organic layers were washed with a saturated sodium bicarbonatesolution (5 mL) and brine (5 mL), dried over magnesium sulfate, andconcentrated in vacou to provide the crude amide. Purification byreverse phase HPLC on a Vydac-18 column provided the desired amide (30mg, 30%). MS (M+Na)⁺=544.

Example 5 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(methoxy)-N-4-(methyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide.

Following a procedure analogous to the preparation of Example 4,compound of Step (2e) (100 mg, 0.20 mmol) was activated and condensedwith N,O-dimethylhydroxylamine hydrochloride (40 mg, 0.40 mmol).Purification by reverse phase HPLC on a Vydac-18 column provided thedesired amide (30 mg, 30%). MS (M+Na)⁺=574.

Example 6 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(methoxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide.

Following a procedure analogous to the preparation of Example 4,compound of Step (2e) (100 mg, 0.20 mmol) was activated and condensedwith O-methylhydroxylamine hydrochloride (40 mg, 0.40 mmol).Purification by reverse phase HPLC on a Vydac-18 column provided thedesired amide (30 mg, 30%). MS (M+Na)⁺=560.

Example 7 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

Following a procedure analogous to the preparation of Example 4,compound of Step (2e) (100 mg, 0.20 mmol) was activated and condensedwith a 2.0 M solution of ammonia in dioxane (0.2 mL, 0.4 mmol).Purification by reverse phase HPLC on a Vydac-18 column provided thedesired amide (30 mg, 30%). MS (M+Na)⁺=530.

Example 7A (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(amino)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Following a procedure analogous to the preparation of Example 4,compound of Step (2e) (100 mg, 0.20 mmol) was activated and condensedwith hydrazine (13 mg, 0.4 mmol). Purification by reverse phase HPLC ona Vydac-18 column provided the desired amide (11.1 mg, 21%). MS(M+Na)⁺=542.

Example 8 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

(8a) Compound 8a was synthesized following a procedure analogous to thepreparation of the compound 1e, but using the caprolactam 2c (2.5 g,5.89 mmol), succinate 9 (1.64 g, 6.0 mmol), and HATU instead of TBTU.The compound was purified by chromatography eluting with 5% methanol inCH₂Cl₂ to afford 1.50 g (45%) of the desired ester.

(8b) The ester from 8a (1.18 g, 2.10 mmol) was dissolved in 10 mL of a50% solution of trifluoroacetic acid in CH₂Cl₂ and stirred at rt for 2h. The solvents were removed by concentration under reduced pressure andthe crude product was dissolved in 10 mL of toluene and reconcentratedtwice to remove residual TFA. The crude acid was used without furtherpurification or characterization.

Following a procedure analogous to the preparation of Example 7,compound 8b (1.065 g, 2.10 mmol) was activated and condensed with anexcess of gaseous ammonia. Purification by reverse phase HPLC on aVydac-18 column provided 500 mg (47%) of the desired compound of Example8. MS (M+Na)⁺=528.

Example 9 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(allyl)-butanediamide

Example 9 was synthesized following a procedure analogous to thepreparation of Example 2, but using succinate 9 (Scheme 2). Purificationby reverse phase HPLC on a Vydac-18 column provided 150 mg of Example 9.MS (M+Na)⁺=544.

Example 10 (2R,3S)N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using2,4-dichlorophenyl boronic acid. Purification afforded 6.0 mg (60%) ofthe desired product. MS (M+Na)⁺=598.

Example 11 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using4-fluorophenyl boronic acid. Purification afforded 5.0 mg (54%) of thedesired product. MS (M+Na)⁺=548.

Example 12 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using4-methylphenyl boronic acid. Purification afforded 3.0 mg (33%) of thedesired product. MS (M+Na)⁺=544.

Example 13 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using4-methoxyphenyl boronic acid. Purification afforded 3.0 mg (32%) of thedesired product. MS (M+Na)⁺=560.

Example 14 (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using3-methylphenyl boronic acid. Purification afforded 3.0 mg (33%) of thedesired product. MS (M+Na)⁺=544.

Example 15 (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using3-chloro-4-fluorophenyl boronic acid. Purification afforded 4.0 mg (41%)of the desired product. MS (M+Na)⁺=582.

Example 16 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using4-trifluoromethylphenyl boronic acid. Purification afforded 4.0 mg (40%)of the desired product. MS (M+Na)⁺=598.

Example 17 (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using3-methoxyphenyl boronic acid. Purification afforded 4.1 mg (44%) of thedesired product. MS (M+Na)⁺=560.

Example 18 (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using3-fluorophenyl boronic acid. Purification afforded 3.5 mg (38%) of thedesired product. MS (M+Na)⁺=548.

Example 19 (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using2-methoxyphenyl boronic acid. Purification afforded 1.3 mg (14%) of thedesired product. MS (M+Na)⁺=560.

Example 20 (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using2-naphthyl boronic acid. Purification afforded 3.0 mg (31%) of thedesired product. MS (M+Na)⁺=580.

It will be understood by one skilled in the art that Scheme 6 can befollowed in a manner analogous to the procedure for Scheme 5.

Example 21 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using4-methoxyphenyl boronic acid. Purification afforded 0.5 mg of thedesired product. MS (M+Na)⁺=544.

Example 22 (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using3-fluorophenyl boronic acid. Purification afforded 1.6 mg of the desiredproduct. MS (M+Na)⁺=532.

Example 23 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using4-trifluoromethylphenyl boronic acid. Purification afforded 0.7 mg(4.3%) of the desired product. MS (M+Na)⁺=582.

Example 24 (2R,3S)N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using2,6-dichlorophenyl boronic acid. Purification afforded 1.8 mg (11%) ofthe desired product. MS (M+Na)⁺=582.

Example 25 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 4-tolylboronic acid. Purification afforded 1.8 mg (12%) of the desired product.MS (M+Na)⁺=528.

Example 26 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using4-methoxyphenyl boronic acid. Purification afforded 0.5 mg (3.3%) of thedesired product. MS (M+Na)⁺=544.

Example 27 (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using4-fluoro-3-chlorophenyl boronic acid. Purification afforded 0.5 mg(3.3%) of the desired product. MS (M+Na)⁺=567.

Example 28 (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using2-methoxyphenyl boronic acid. Purification afforded 0.8 mg (5.3%) of thedesired product. MS (M+Na)⁺=544.

Example 29 (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using2-methoxyphenyl boronic acid. Purification afforded 1.5 mg (10%) of thedesired product. MS (M+Na)⁺=544.

It will be understood by one skilled in the art that Scheme 7 can befollowed in a manner analogous to the procedure for Schemes 5 and 6.

Example 30 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

Amide 35 of Scheme 7 (0.10 g, 0.18 mmol) was dissolved in 5 mL oftoluene and 41 mg (0.27 mmol) of 4-methoxyphenyl boronic acid was added,followed by 31 mg (0.0147 mmol) oftetrakis(triphenylphosphine)palladium, 0.5 mL of a 2M sodium carbonatesolution and 0.5 mL of methanol. The reaction solution was heated toreflux for 16 h and then allowed to cool to rt. The reaction solutionwas diluted with 10 mL of water and extracted 2× with 50 mL of ethylacetate. The combined organic layers were dried and concentrated and theresulting oil was purified by chromatography eluting with 30 to 100%ethyl acetate in hexanes as a solvent to provide 30 mg (29%) of biarylproduct. MS (M+H)⁺=580.

The purified biaryl product was dissolved in 10 mL of 1:1trifluoroacetic acid/CH₂Cl₂ and stirred at rt for 2 h. The solvents werethen removed under reduced pressure and the resulting oil wasredissolved in 5 mL of toluene and reconcentrated to remove residualTFA. The crude acid (25 mg, 0.047 mmol) was then dissolved in 1 mL ofDMF and 10 mL of N-methylmorpholine (0.094 mmol) and 42 mg (0.062 mmol)HATU were added and the reaction solution was stirred at rt for 45 min.Gaseous ammonia was then bubbled in at a gentle rate for about 1 minuteand the solution was stirred for an additional 1 min. The reactionsolution was then diluted with 10 mL of water and extracted 3× with 30mL of ethyl acetate. The combined organic layers were dried andconcentrated under reduced pressure to a solid which was purified byreversed phase HPLC to provide 3.5 mg (10%) of the compound of Example30 as its trifluoroacetic acid salt. MS (M+H)⁺=523.

Example 31 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for the compound of Example 30 wasfollowed using 4-trifluoromethylphenyl boronic acid. Purification byHPLC afforded 6.0 mg of the desired product from as its trifluoroaceticacid salt. MS (M+Na)⁺=583.

Example 32 (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

Amide 35 (0.30 g, 0.54 mmol) was dissolved in 3 mL of DMF and 123 mg(0.70 mmol) of 4-methoxyphenyl boronic acid was added, followed by 44 mg(0.0543 mmol) of bis(diphenylphosphinoferrocene) palladim (II)dichloride and 1.0 mL (7.18 mmol) of triethylamine. The reactionsolution was heated to 80° C. for 24 h and then allowed to cool to rt.The reaction solution was diluted with 10 mL of water and extracted 2×with 50 mL of ethyl acetate. The combined organic layers were dried andconcentrated and the resulting oil was purified by chromatographyeluting with 20 to 100% ethyl acetate in hexanes as a solvent to provide140 mg (50%) of biaryl product. MS (M+Na)⁺=624.

The general procedure reported for the compound of Example 30 was thenfollowed to provide the amide. Purification by chromatography elutingwith 20 to 100% ethyl acetate in hexanes afforded 45 mg of the desiredproduct of Example 32 as its trifluoroacetic acid salt. MS (M+Na)⁺=567.

Example 33 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(butyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 8 was followed usingbutylamine. Analysis by ¹HNMR integration relative to an internalstandard revealed a yield of 100% of the desired product. MS(M+Na)⁺=586.

Example 34 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(2-furylmethyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 8 was followed using2-furylmethylamine. Analysis by ¹HNMR integration relative to aninternal standard revealed a yield of 75% of the desired product. MS(M+Na)⁺=610.

Example 35 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(cyclopentyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 8 was followed usingcyclopentylamine. Analysis by ¹HNMR integration relative to an internalstandard revealed a yield of 42% of the desired product. MS (M+Na)⁺=598.

Example 36 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(cinnamyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 8 was followed usingcinnamylamine. Analysis by ¹HNMR integration relative to an internalstandard revealed a yield of 100% of the desired product. MS(M+Na)⁺=646.

Example 37 (2R,3S)N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide

3-Bromomethylbenzophenone. A solution of 3-methylbenzophenone (20 g, 102mmol) dissolved in 40 mL of 1,2-dibromoethane was heated to reflux. Overa period of about 3 hours a solution of 105 mmol of bromine dissolved in6 mL of 1,2-dibromoethane was added to the refluxing solution. After theaddition was complete the solution was allowed to cool to rt and dilutedwith 100 mL of dichloromethane. The organic layer was extracted with1×25 mL of 1 N HCl, 2×15 mL of NaHCO₃ Solution, and 2×25 ML of brine.The organic layers were dried over magnesium sulfate and concentrated invacuo. The residue was then distilled to afford the product, 16.5 g(60%) as an oil that solidified upon standing, b.p. 160° C. at 300mTorr. ¹H NMR analysis shows that the product contains approximately 7%of the dibromide.

3-(1,1-dimethylethylcarbomethoxy-N-(benzophenone-3-yl-methyl)caprolactam.Diisopropylamine (4.2 mL, 30 mmol) was dissolved in 25 mL of THF andchilled to −78° C. To the solution was added 10 mL of 2.5Mn-butyllithium in hexanes and the solution was warmed to 0° C. andallowed to stir for 10 min. A solution of Boc-protected aminocaprolactam1a (5.0 grams, 22 mmol) dissolved in 25 mL of THF was then added and thereaction solution was stirred for 1 h at 0° C. Solid3-bromomethyl-benzophenone was then added and the reaction solution wasallowed to warm to rt and stir overnight. The reaction solution wasdiluted with water and extracted into ethyl acetate (100 mL). Theorganic layer was rinsed with 2×25 mL of 1 N HCl, 2×25 mL of saturatedNaHCO₃ and 2×25 mL of brine, dried over magnesium sulfate, and dried invacuo. Chromatography eluting with a gradient of 30% to 40% ethylacetate in hexanes afforded the pure benzophenone-substitutedcaprolactam derivative (7.4 g, 80%). MS (M+Na)⁺=445.

The compound of Example 10 was synthesized in a manner analagous to thesynthesis of the compound of Example 8 using succinate 9 and thebenzophenone-substituted caprolactam derivative. The compound waspurified by crystallization from ethyl acetate to afford 0.26 g ofcrystals. MS (M+Na)+=540.

Example 38 (2R,3S)N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The compound of Example 11 was synthesized in a manner analagous to thesynthesis of the compound of Example 8 using succinate 10 and thebenzophenone-substituted caprolactam derivative. The compound waspurified by crystallization from ethyl acetate to afford 0.25 g ofcrystals. MS (M+Na)+=542.

Example 39 (2R,3S)N1-[(3S)-hexahydro-1-(4-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

(39-a)3-(1,1-dimethylethylcarbomethoxy-N-(4-bromophenylmethyl)caprolactam. Thetitle compound was synthesized in a manner analogous to the preparationof3-(1,1-dimethylethylcarbomethoxy-N-(benzophenone-3-yl-methyl)caprolactamin Example 10 but using 4-bromobenzyl bromide as the alkylaing agent.The compound was purified by chromatography eluting with 5-20% ethylacetate in hexanes as eluent to provide 7.0 g (70%) of the titlecompound as a solid. MS (M+Na)+=419.

(39-b)3-(1,1-dimethylethylcarbomethoxy-N-(4,-(4′-trifluoromethylphenyl)phenylmethyl)caprolactam.To a solution of3-(1,1-dimethylethylcarbomethoxy-N-(4-bromophenylmethyl)caprolactam (0.5g, 1.26 mmol) dissolved in 10 mL of toluene was added 263 mg (1.38 mmol)of 4-trifluoromethylphenyl boronic acid, 1 mL of methanol, and 1 mL of a2M solution of potassium carbonate. The solution was degassed bynitrogen bubbling for 5 min, and then 33 mg oftris(dibenzylideneacetone)dipalladium (0) chloroform adduct and 66 mg oftriphenylphosphine was added. The solution ws heated to reflux for 16 hand then allowed to cool and diluted with 20 mL of water. The aqueouslayer was extracted 3× with 25 mL of ethyla acetate and concentrated.The resulting oil was purified by chromatography eluting with 20% ethylacetate in hexanes to afford 0.47 g (81%) of an oil which crystallizedon standing.

(39-d) The compound 39-d was synthesized in a manner analagous to thesynthesis of the compound of Example 8 using succinate 10 (280 mg, 1.04mmol) and3-(1,1-dimethylethylcarbomethoxy-N-(4,-(4′-trifluoromethylphenyl)-phenylmethyl)caprolactam.The compound was purified by chromatography eluting with 20-100% ethylacetate in hexanes to afford 40 mg of a white powder. MS (M+H)+=560.

Example 40 (2S,3R)N1-[(3S)-hexahydro-1-(3-(2-tetrazolylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(propyl)-3-(2-methylpropyl)-butanediamide

(40-a) The compound of Example 40 was synthesized in a manner analogousto the synthesis of the compound of Example 39, but using thesubstituted acid 28 of Scheme 6 (50 mg, 0.10 mmol) ando-((N-trityl)-tetrazole)phenylboronic acid under the conditions for theformation of the compound (39-b). The desired biaryl acid was isolatedas an impure mixture (134 mg) and used directly in the next step.

(40-b) The acid 40-a (134 mg, impure mixture) was converted to the amideunder the conditions reported for the compound of Example 8. The crudeamide was then dissolved in 2 mL of 10% trifluoroacetic acid in methanoland allowed to stir at rt for 30 min. The solvents were removed and theresidue was purified by chromatography eluting with 10% methanol inethyl acetate to provide 40 mg (71%, 2 steps) of the compound of Example40 as a sticky powder. MS (M+Na)+=582.

Example 41 (2S,3R)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(propyl)-3-(2-methylpropyl)-butanediamide

(41-a) The compound of Example 41 is formed by coupling Succinate 23(480 mg, 1.21 mmol) with the substituted caprolactam TFA salt 2c underthe conditions reported for the synthesis of the compound of Example 8.The crude fluorenylmethyl ester was used in the next step with outfurther purification. MS (M+Na)+=709.

(41-b) The crude fluorenylmethyl ester is dissolved in 2 mL of a 50%solution of piperidine in CH₂Cl₂ and stirred for 3 h at rt. A 10 mLportion of 1N HCl was then added and the mixture was extracted 3× with10 mL of ethyl acetate. The crude acid was used in the next step without further purification. MS (M+H)+=509.

The compound of Example 41 was then prepared using the acid 41-b underthe conditions reported for compound of Example 28. The compound waspurified by chromatography eluting with 5% methanol in CH₂Cl₂ to afford120 mg (19%, 3 steps) of a white powder. MS (M+H)+=508.

Example 42 (2S,3R)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide

3-Phenoxybenzyl iodide: To a solution of 3-phenoxybenzyl chloride (10.0g, 45.7 mmol) in 200 ml acetone was added sodium iodide (7.6 g, 507mmol). The mixture was stirred at temperature overnight. The mixture wasdiluted with 300 ml hexane and the organic layer was washed twice with5% sodium bicarbonate, once with brine and then dried over MgSO₄.Evaporation of the filtrate gave a light yellow oil. The product wasused in next step without purification. ¹H NMR (CDCl₃) 4.4 (s,2H),6.8-7.4 (m, 9H).

Synthesis of Example 42:

To a solution of benzodiazepine 50 (910 mg, 3.63 mmol), succinate 9 (980mg, 3.63 mmol), hydroxybenzotriazole (980 mg., 7.25 mmol) and EDC (870mg, 4.54 mmol) in 100 ml CH₂Cl₂ at 0 degrees was added triethylamine(0.76 ml, 5.45 mmol). The reaction mixture was washed with saturatedsodium bicarbonate solution, 1.0N HCl, brine and dried over MgSO₄.Evaporation of the organic layer and purification by columnchromatography on silica gel with hexane-ethyl acetate (7:3) gave 610 mgof benzodiazepine 51 as a white solid. M+H=504.37. ¹H NMR (CDCl₃)0.8-1.0 (m, 6H), 1.0-1.2 (m, 1H), 1.4-1.5 (d, 9H), 1.6-1.9 (m, 2H),2.2-2.8 (m, 4H), 4.9-5.2 (m, 2H), 5.6 (dd, 1H), 5.6-6.0 (m, 1H), 7.0-7.6(m, 9H).

To a solution of benzodiazepine 51 (440 mg, 0.875 mmol) in DMF (20 ml)at 0 degrees was added NaH (45 mg, 1.12 mmol). The mixture was stirredat 0 degrees for 1.5 hr and then a solution of 3-phenoxylbenzyl iodide(330 mg, 1.06 mmol) in 10 ml DMF was added dropwise. The reactionmixture was allowed to warm to room temperature and stirred overnight.TLC using hexanes:EtOAc 6:4 (product Rf=0.31) indicated that thereaction was complete. The reaction mixture was quenched with water, andthe solvent was evaporated under high vacuum, which provided a viscousyellow oil. The product benzodiazepine 52 was dissolved in ethylacetate, which was washed with water (2×), brine and then dried overMgSO_(4.)

Evaporation of solvent gave 600 mg of benzodiazepine 52 as a yellow oilwhich was not further purified. M+H=686.3, M+Na=708.3. ¹H NMR (CDCl₃)0.8-1.0 (m, 6H), 1.0-1.3 (m, 1H), 1.4-1.5 (d, 9H), 1.5-1.9 (2H), 2.2-2.7(4H), 4.6-4.8 (d,1H), 4.9-5.2 (m, 2H), 5.6-5.9 (m, 3H), 6.6-7.6 (m,18H).

A solution of benzodiazepine 52 in 40 ml of TFA/CH₂Cl₂ (1:1) was stirredovernight at room temperature then evaporated to dryness. Repeatedaddition of toluene and evaporation provided 560 mg. of 53 as a yellowsolid. (M−H=629.1)

To a solution of benzodiazepine 53 and HATU (410 mg, 1.08 mmol) in 30 mlDMF was added diisopropylethylamine (0.6 ml, 3.44 mmol) at 0 degrees.After 10 minutes, ammonia gas was bubbled through the solution for twominutes, and the reaction mixture was allowed to warm to roomtemperature and stirred overnight. Addition of water and solventevaporation under high vacuum provided a yellow solid. The solid wastaken up in ethyl acetate-water (1:1), and the organic layer was washedwith water (2×), brine and then dried over MgSO₄. Evaporation of solventgave a light yellow solid. Chromatographic purification on silica gelusing CH₂Cl₂: methanol (10:0.5) gave 256 mg of Example 42. M+H=629.2HNMR (CDCl₃) 0.8-1.0 (m, 6H), 1.2-1.4 (m, 1H), 1.6-2.0 (m, 2H),2.2-2.8(4H), 4.6-4.8 (m, 1H), 5.0-5.2(m, 2H), 5.6-5.9 (m, 3H), 6.2-7.8(m, 18H).

Example 43 (2R)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-butanediamide

Step (43a): The compound of Step (43a) is formed by coupling succinate 7(115 mg, 0.5 mmol) with the substituted caprolactam TFA salt (212 mg,0.5 mmol) from Step (2c) of Example 2 under the conditions reported forthe synthesis of the compound of Example 8. The crude tert-butyl esterwas taken on without further purification.

Step (43b): The compound of Step (43b) is formed by dissolving the crudeproduct from Step (43a) in 5 mL of a 1:1 solution of TFA/CH₂Cl₂ andstirring at room temperature for 2 hours. Concentration followed byreconcentration twice from 10 mL of toluene provides the crude acidwhich was taken on with no further purification.

Step (43c): The title compound, Example 43, was prepared using the acidfrom Step (43b) under the conditions reported for the compound ofExample 7. The compound was purified by chromatography eluting with 5%methanol in CH₂Cl₂ to afford 50 mg (21%, 3 steps) of a white powder. MS(M+Na)⁺=488.

Utility

Aβ production has been implicated in the pathology of Alzheimer'sDisease (AD). The compounds of the present invention have utility forthe prevention and treatment of AD by inhibiting Aβ production. Methodsof treatment target formation of Aβ production through the enzymesinvolved in the proteolytic processing of β-amyloid precursor protein.Compounds that inhibit b or g secretase activity, either directly orindirectly, control the production of Aβ. Such inhibition of β or γsecretases reduces production of Aβ, and is expected to reduce orprevent the neurological disorders associated with Aβ protein, such asAlzheimer's Disease.

Cellular screening methods for inhibitors of Aβ production, testingmethods for the in vivo suppression of Aβ production, and assays for thedetection of secretase activity are known in the art and have beendisclosed in numerous publications, including PCT publication number WO98/22493, EPO publication number 0652009, U.S. Pat. Nos. 5,703,129 and5,593,846; all hereby incorporated by reference.

The compounds of the present invention have utility for the preventionand treatment of disorders involving Aβ production, such ascerebrovascular disorders.

Compounds of the present invention have been shown to inhibit Aβproduction, as determined by the secretase inhibition assay describedbelow.

Compounds of the present invention have been shown to inhibit Aβproduction, utilizing the C-terminus b amyloid precursor proteinaccumulation assay described below.

Compounds of Formula (I) are expected to possess γ-secretase inhibitoryactivity. The γ-secretase inhibitory activity of the compounds of thepresent invention is demonstrated using assays for such activity, forExample, using the assay described below. Compounds of the presentinvention have been shown to inhibit the activity of γ-secretase, asdetermined by the Aβ immunoprecipitation assay.

Compounds provided by this invention should also be useful as standardsand reagents in determining the ability of a potential pharmaceutical toinhibit Aβ production. These would be provided in commercial kitscomprising a compound of this invention.

As used herein “μg” denotes microgram, “mg” denotes milligram, “g”denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L”denotes liter, “nM” denotes nanomolar, “μM” denotes micromolar, “mM”denotes millimolar, “M” denotes molar, “nm” denotes nanometer, “SDS”denotes sodium dodecyl sulfate, and “DMSO” denotes dimethyl sulfoxide,and “EDTA” denotes ethylenediaminetetraacetato.

A compound is considered to be active if it has an IC₅₀ or K_(i) valueof less than about 100 μM for the inhibition of Aβ production orinhibition of proteolytic activity leading to Aβ production. Compounds,as demonstrated by use of the invention, have demonstrated IC₅₀ values,for the inhibition of Aβ production, of less than about 100 μM.Preferably compounds, as demonstrated by use of the invention,demonstrate IC₅₀ values, for the inhibition of Aβ production, of lessthan about 1 μM. More preferably compounds, as demonstrated by use ofthe invention, demonstrate IC₅₀ values, for the inhibition of Aβproduction, of less than about 100 nM. Even more preferably compounds,as demonstrated by use of the invention, demonstrate IC₅₀ values, forthe inhibition of Aβ production, of less than about 50 nM.

β Amyloid Precursor Protein Accumulation Assay (βAPPA Assay)

An assay to evaluate the accumulation of Aβ protein was developed todetect potential inhibitors of secretases. The assay uses the N 9 cellline, characterized for expression of exogenous APP by immunoblottingand immunoprecipitation.

The effect of test compounds on the accumulation of Aβin the conditionedmedium is tested by immunoprecipitation. N 9 cells are grown toconfluency in 6-well plates and washed twice with 1× Hank's bufferedsalt solution. The cells are starved in methionine/cysteine deficientmedia for 30 min., followed by replacement with fresh deficient mediacontaining 150 uCi Tran35S-LABEL™ (ICN). Test compounds dissolved inDMSO (final concentration 1%) are added, over a range of 1 picomolar to100 micromolar, together with the addition of the fresh media containingTran35S-LABEL™. The cells are incubated for 4 h at 37° C. in a tissueculture incubator.

At the end of the incubation period, the conditioned medium is harvestedand pre-cleared by the addition of 5 μl normal mouse serum and 50 ul ofprotein A Sepharose (Pharmacia), mixed by end-over-end rotation for 30minutes at 4° C., followed by a brief centrifugation in a microfuge. Thesupernatant is then harvested and transferred to fresh tubes containing5 ug of a monoclonal antibody (examples of antibodies include but arenot limited by, clone 1101.1, directed against an internal peptidesequence in Aβ; or 6E10 from Senetek; or 4G8 from Senetek; additionallypolyclonals from rabbit antihuman Aβ from Boehringer Mannheim) and 50 μlprotein A Sepharose. After incubation overnight at 4° C., the samplesare washed three times with high salt washing buffer (50 mM Tris, pH7.5, 500 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40), three times with lowsalt wash buffer (50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM EDTA, 0.5%Nonidet P-40), and three times with 10 mM Tris, pH 7.5. The pellet afterthe last wash is resuspended in SDS sample buffer (Laemmli U.K. Cleavageof structural proteins during the assembly of the head of bacteriphageT4. Nature 227, 680-5, 1970.) and boiled for 3 minutes. The supernatantis then fractionated on either 10-20% Tris/Tricine SDS gels or on 16.5%Tris/Tricine SDS gels. The gels are dried and exposed to X-ray film oranalyzed by phosphorimaging. The resulting image is analyzed for thepresence of Aβ polypeptides. The steady-state level of Aβ in thepresence of a test compound is compared to wells treated with DMSO (1%)alone. A typical test compound in this assay blocks Aβ accumulation inthe conditioned medium, and is considered active with an IC₅₀ less than100 μM.

C-Terminus β-Amyloid Precursor Protein Accumulation Assay (CTF Assay)

The effect of test compounds on the accumulation of C-terminal fragmentsis determined by immunoprecipitation of APP and fragments thereof fromcell lysates. N 9 cells are metabolically labeled, as above, with mediacontaining Tran35S-LABEL™, in the presence or absence of test compounds.At the end of the incubation period, the conditioned medium areharvested and cells lysed in RIPA buffer (10 mM Tris, pH 8.0 containing1% Triton X-100, 1% deoxycholate, 0.1% SDS, 150 mM NaCl, 0.125% NaN₃).Again, lysates are precleared with 5 ul normal rabbit serum/50 ulprotein A Sepharose, followed by the addition of BC-1 antiserum (15 μl;)and 50 μl protein A Sepharose for 16 hours at 4° C. Theimmunoprecipitates are washed as above, bound proteins eluted by boilingin SDS sample buffer and fractionated by Tris/Tricine SDS-PAGE. Afterexposure to X-ray film or phosphorimager, the resulting images areanalyzed for the presence of C-terminal APP fragments. The steady-statelevel of C-terminal APP fragments is compared to wells treated with DMSO(1%) alone. A typical test compound in this assay stimulates C-terminalfragment accumulation in the cell lysates, and is considered active withan IC₅₀ less than 100 μM.

Accumulation-Release Assay

This immunoprecipitation assay is specific for g secretase activity(i.e., proteolytic activity required to generate the C-terminal end ofAβ either by direct cleavage or generating a C-terminal extended specieswhich is subsequently further proteolyzed). N 9 cells are pulse labeledwith media containing Tran35S-LABEL™ in the presence of a reported gsecretase inhibitor (MDL 28170; Higaki J, Quon D, Zhong Z, Cordell B.Inhibition of beta-amyloid formation identifies proteolytic precursorsand subcellular site of catabolism. Neuron 14, 651-659, 1995) for 1 h,followed by washing to remove ³⁵S radiolabel and MDL 28170. The media isreplaced and test compounds are added over a dose range (for example 0.1nM to 100 uM). The cells are chased for increasing periods of times andAβ is isolated from the conditioned medium and C-terminal fragments fromcell lysates (see accumulation assay above). The activity of testcompounds are characterized by whether a stabilization of C-terminalfragments is observed and whether Aβ is generated from these accumulatedprecursor. A typical test compound in this assay prevents the generationof Aβ out of accumulated C-terminal fragments and is considered activewith an IC₅₀ less than 100 μM.

Dosage and Formulation

The compounds determined from the present invention can be administeredorally using any pharmaceutically acceptable dosage form known in theart for such administration. The active ingredient can be supplied insolid dosage forms such as dry powders, granules, tablets or capsules,or in liquid dosage forms, such as syrups or aqueous suspensions. Theactive ingredient can be administered alone, but is generallyadministered with a pharmaceutical carrier. A valuable treatise withrespect to pharmaceutical dosage forms is Remington's PharmaceuticalSciences, Mack Publishing.

The compounds determined from the present invention can be administeredin such oral dosage forms as tablets, capsules (each of which includessustained release or timed release formulations), pills, powders,granules, elixirs, tinctures, suspensions, syrups, and emulsions.Likewise, they may also be administered in intravenous (bolus orinfusion), intraperitoneal, subcutaneous, or intramuscular form, allusing dosage forms well known to those of ordinary skill in thepharmaceutical arts. An effective but non-toxic amount of the compounddesired can be employed to prevent or treat neurological disordersrelated to β-amyloid production or accumulation, such as Alzheimer'sdisease and Down's Syndrome.

The compounds of this invention can be administered by any means thatproduces contact of the active agent with the agent's site of action inthe body of a host, such as a human or a mammal. They can beadministered by any conventional means available for use in conjunctionwith pharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents. They can be administered alone, butgenerally administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice.

The dosage regimen for the compounds determined from the presentinvention will, of course, vary depending upon known factors, such asthe pharmacodynamic characteristics of the particular agent and its modeand route of administration; the species, age, sex, health, medicalcondition, and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment; the frequency of treatment;the route of administration, the renal and hepatic function of thepatient, and the effect desired. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent, counter, or arrest the progress of thecondition.

Advantageously, compounds determined from the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three, or four times daily.

The compounds identified using the present invention can be administeredin intranasal form via topical use of suitable intranasal vehicles, orvia transdermal routes, using those forms of transdermal skin patcheswall known to those of ordinary skill in that art. To be administered inthe form of a transdermal delivery system, the dosage administrationwill, of course, be continuous rather than intermittent throughout thedosage regimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients, orcarriers (collectively referred to herein as carrier materials) suitablyselected with respect to the intended form of administration, that is,oral tablets, capsules, elixirs, syrups and the like, and consistentwith conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor β-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds determined from the present invention can also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamallar vesicles, and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compoundsdetermined from the present invention may be coupled to a class ofbiodegradable polymers useful in achieving controlled release of a drug,for example, polylactic acid, polyglycolic acid, copolymers ofpolylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans,polycyanoacylates, and crosslinked or amphipathic block copolymers ofhydrogels.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract. Liquid dosage forms fororal administration can contain coloring and flavoring to increasepatient acceptance. In general, water, a suitable oil, saline, aqueousdextrose (glucose), and related sugar solutions and glycols such aspropylene glycol or polyethylene glycols are suitable carriers forparenteral solutions. Solutions for parenteral administration preferablycontain a water soluble salt of the active ingredient, suitablestabilizing agents, and if necessary, buffer substances. Antioxidizingagents such as sodium bisulfite, sodium sulfite, or ascorbic acid,either alone or combined, are suitable stabilizing agents. Also used arecitric acid and its salts and sodium EDTA. In addition, parenteralsolutions can contain preservatives, such as benzalkonium chloride,methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

The Tables below provide representative Examples of the compounds ofFormula (I) of the present invention.

TABLE 1

Ex # R¹ R² R³ Z—Y—X—W  1 H OH propyl 3,3-diphenylpropyl  2 H OH propyl3-phenoxybenzyl  3 H OH propyl phenyl  4 H CH₃ propyl 3-phenoxybenzyl  5CH₃ OCH₃ propyl 3-phenoxybenzyl  6 H OCH₃ propyl 3-phenoxybenzyl  7 H Hpropyl 3-phenoxybenzyl  7A H NH₂ propyl 3-phenoxybenzyl  8 H H allyl3-phenoxybenzyl  9 H OH allyl 3-phenoxybenzyl 10 H OH propyl3-(2,4-dichlorophenyl)- benzyl 11 H OH propyl 3-(4-fluorophenyl)-benzyl12 H OH propyl 3-(4-methylphenyl)-benzyl 13 H OH propyl3-(4-methoxyphenyl)-benzyl 14 H OH propyl 3-(3-methylphenyl)-benzyl 15 HOH propyl 3-(3-chloro-4- fluorophenyl)-benzyl 16 H OH propyl3-(4-trifluoromethyl- phenyl)benzyl 17 H OH propyl3-(3-methoxyphenyl)-benzyl 18 H OH propyl 3-(3-fluorophenyl)-benzyl 19 HOH propyl 3-(2-methoxyphenyl)-benzyl 20 H OH propyl 3-(2-naphthyl)benzyl21 H H propyl 3-(4-methoxyphenyl)-benzyl 22 H H propyl3-(3-fluorophenyl)-benzyl 23 H H propyl 3-(4-F₃C-phenyl)benzyl 24 H Hpropyl 3-(2,4-Cl₂-phenyl)benzyl 25 H H propyl 3-(4-H₃C-phenyl)benzyl 26H H propyl 3-(4-H₃CO-phenyl)benzyl 27 H H propyl3-(3-Cl,4-F-phenyl)-benzyl 28 H H propyl 3-(3-H₃CO-phenyl)benzyl 29 H Hpropyl 3-(2-H₃CO-phenyl)benzyl 30 H H propyl 3-(4-H₃CO-phenyl)-pyrid-5-ylmethyl 31 H H propyl 3-(4-F₃C-phenyl)-pyrid-5- ylmethyl 32 H H propyl3-(3-Cl,4-F-phenyl)-pyrid- 5-ylmethyl 33 H n-butyl propyl3-phenoxybenzyl 34 H 2- propyl 3-phenoxybenzyl furyl methyl 35 H C₅H₉propyl 3-phenoxybenzyl 36 H cinnamyl propyl 3-phenoxybenzyl 37 H H allylbenzophenone-3-yl-methyl 38 H H propyl benzophenone-3-yl-methyl 39 H Hpropyl 4-(4-F₃C-phenyl)benzyl 40* H H i-butyl 3-(2-tetrazolyl-phenyl)-R⁵ = propyl benzyl 41* H H i-butyl 3-phenoxybenzyl R⁵ = propyl 43 H H H3-phenoxybenzyl *For these compounds the i-butyl substituent on thecarbon adjacent to CR³ in the captioned FIGURE is actually n-propyl.

Table 2 demonstrates representative compounds envisaged within the scopeof the present invention. Each formulae at the start of Table 2 areintended to be paired with each entry in the table which follows.

For example the compound (2R,3S)N1-[(3S)-hexahydro-1-(3-(3,4-dimethoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamideis represented by Example #139-A-j, which comprises the core A,succinate i, and entry #139.

For example the compound (2R,3S)N1-[6,7-dihydro-5-(3-(3,4-dimethoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamideis represented by Example #139-B-j, which comprises the core B,succinate j, and entry #139.

For example the compound (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3,4-dimethoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide,is represented by Example #139-C-ab, which comprises the core C,succinate ab, and entry #139.

wherein R³ and R⁵ are:

Ex# W X Y Z 100 —CH₂— phen-1,3-diyl bond phenyl 101 —CH₂— phen-1,3-diylbond 3,3- diphenylmethyl 102 —CH₂— phen-1,3-diyl bond 2-F-phenyl 103—CH₂— phen-1,3-diyl bond 3-F-phenyl 104 —CH₂— phen-1,3-diyl bond4-F-phenyl 105 —CH₂— phen-1,3-diyl bond 2-Cl-phenyl 106 —CH₂—phen-1,3-diyl bond 3-Cl-phenyl 107 —CH₂— phen-1,3-diyl bond 4-Cl-phenyl108 —CH₂— phen-1,3-diyl bond 2-Me-phenyl 109 —CH₂— phen-1,3-diyl bond3-Me-phenyl 110 —CH₂— phen-1,3-diyl bond 4-Me-phenyl 111 —CH₂—phen-1,3-diyl bond 2-MeO-phenyl 112 —CH₂— phen-1,3-diyl bond3-MeO-phenyl 113 —CH₂— phen-1,3-diyl bond 4-MeO-phenyl 114 —CH₂—phen-1,3-diyl bond 2-MeS-phenyl 115 —CH₂— phen-1,3-diyl bond3-MeS-phenyl 116 —CH₂— phen-1,3-diyl bond 4-MeS-phenyl 117 —CH₂—phen-1,3-diyl bond 2-F₃C-phenyl 118 —CH₂— phen-1,3-diyl bond3-F₃C-phenyl 119 —CH₂— phen-1,3-diyl bond 4-F₃C-phenyl 120 —CH₂—phen-1,3-diyl bond 2,3-diF-phenyl 121 —CH₂— phen-1,3-diyl bond2,4-diF-phenyl 122 —CH₂— phen-1,3-diyl bond 2,5-diF-phenyl 123 —CH₂—phen-1,3-diyl bond 2,6-diF-phenyl 124 —CH₂— phen-1,3-diyl bond3,4-diF-phenyl 125 —CH₂— phen-1,3-diyl bond 3,5-diF-phenyl 126 —CH₂—phen-1,3-diyl bond 2,3-diCl-phenyl 127 —CH₂— phen-1,3-diyl bond2,4-diCl-phenyl 128 —CH₂— phen-1,3-diyl bond 2,5-diCl-phenyl 129 —CH₂—phen-1,3-diyl bond 2,6-diCl-phenyl 130 —CH₂— phen-1,3-diyl bond3,4-diCl-phenyl 131 —CH₂— phen-1,3-diyl bond 3,5-diCl-phenyl 132 —CH₂—phen-1,3-diyl bond 2-Cl-3-F-phenyl 133 —CH₂— phen-1,3-diyl bond2-Cl-4-F-phenyl 134 —CH₂— phen-1,3-diyl bond 2-Cl-5-F-phenyl 135 —CH₂—phen-1,3-diyl bond 3-Cl-4-F-phenyl 136 —CH₂— phen-1,3-diyl bond3-Cl-5-F-phenyl 137 —CH₂— phen-1,3-diyl bond 4-Cl-2-F-phenyl 138 —CH₂—phen-1,3-diyl bond 4-Cl-3-F-phenyl 139 —CH₂— phen-1,3-diyl bond2,3-diMeO-phenyl 140 —CH₂— phen-1,3-diyl bond 2,4-diMeO-phenyl 141 —CH₂—phen-1,3-diyl bond 2,5-diMeO-phenyl 142 —CH₂— phen-1,3-diyl bond2,6-diMeO-phenyl 143 —CH₂— phen-1,3-diyl bond 3,4-diMeO-phenyl 144 —CH₂—phen-1,3-diyl bond 3,5-diMeO-phenyl 145 —CH₂— phen-1,3-diyl bondcyclopropyl 146 —CH₂— phen-1,3-diyl bond cyclobutyl 147 —CH₂—phen-1,3-diyl bond cyclopentyl 148 —CH₂— phen-1,3-diyl bond cyclohexyl149 —CH₂— phen-1,3-diyl bond 2-furanyl 150 —CH₂— phen-1,3-diyl bond2-thienyl 151 —CH₂— phen-1,3-diyl bond 2-imidazolyl 152 —CH₂—phen-1,3-diyl bond 2-pyridyl 153 —CH₂— phen-1,3-diyl bond 3-pyridyl 154—CH₂— phen-1,3-diyl bond 4-pyridyl 155 —CH₂— phen-1,3-diyl bondN-morpholinyl 156 —CH₂— phen-1,3-diyl bond N-piperidinyl 157 —CH₂—phen-1,3-diyl bond 3-Me-2-pyridyl 158 —CH₂— phen-1,3-diyl bond4-Me-2-pyridyl 159 —CH₂— phen-1,3-diyl bond 1-indolyl 160 —CH₂—phen-1,3-diyl bond 2-benzothienyl 161 —CH₂— phen-1,3-diyl bond2-benzofuranyl 162 —CH₂— phen-1,3-diyl bond 1-benzimidazole 163 —CH₂—phen-1,3-diyl bond 2-naphthyl 164 —CH₂— pyridin-3, bond phenyl 5-diyl165 —CH₂— pyridin-3, bond 3,3- 5-diyl diphenylmethyl 166 —CH₂—pyridin-3, bond 2-F-phenyl 5-diyl 167 —CH₂— pyridin-3, bond 3-F-phenyl5-diyl 168 —CH₂— pyridin-3, bond 4-F-phenyl 5-diyl 169 —CH₂— pyridin-3,bond 2-Cl-phenyl 5-diyl 170 —CH₂— pyridin-3, bond 3-Cl-phenyl 5-diyl 171—CH₂— pyridin-3, bond 4-Cl-phenyl 5-diyl 172 —CH₂— pyridin-3, bond2-Me-phenyl 5-diyl 173 —CH₂— pyridin-3, bond 3-Me-phenyl 5-diyl 174—CH₂— pyridin-3, bond 4-Me-phenyl 5-diyl 175 —CH₂— pyridin-3, bond2-MeO-phenyl 5-diyl 176 —CH₂— pyridin-3, bond 3-MeO-phenyl 5-diyl 177—CH₂— pyridin-3, bond 4-MeO-phenyl 5-diyl 178 —CH₂— pyridin-3, bond2-MeS-phenyl 5-diyl 179 —CH₂— pyridin-3, bond 3-MeS-phenyl 5-diyl 180—CH₂— pyridin-3, bond 4-MeS-phenyl 5-diyl 181 —CH₂— pyridin-3, bond2-F₃C-phenyl 5-diyl 182 —CH₂— pyridin-3, bond 3-F₃C-phenyl 5-diyl 183—CH₂— pyridin-3, bond 4-F₃C-phenyl 5-diyl 184 —CH₂— pyridin-3, bond2,3-diF-phenyl 5-diyl 185 —CH₂— pyridin-3, bond 2,4-diF-phenyl 5-diyl186 —CH₂— pyridin-3, bond 2,5-diF-phenyl 5-diyl 187 —CH₂— pyridin-3,bond 2,6-diF-phenyl 5-diyl 188 —CH₂— pyridin-3, bond 3,4-diF-phenyl5-diyl 189 —CH₂— pyridin-3, bond 3,5-diF-phenyl 5-diyl 190 —CH₂—pyridin-3, bond 2,3-diCl-phenyl 5-diyl 191 —CH₂— pyridin-3, bond2,4-diCl-phenyl 5-diyl 192 —CH₂— pyridin-3, bond 2,5-diCl-phenyl 5-diyl193 —CH₂— pyridin-3, bond 2,6-diCl-phenyl 5-diyl 194 —CH₂— pyridin-3,bond 3,4-diCl-phenyl 5-diyl 195 —CH₂— pyridin-3, bond 3,5-diCl-phenyl5-diyl 196 —CH₂— pyridin-3, bond 2-Cl-3-F-phenyl 5-diyl 197 —CH₂—pyridin-3, bond 2-Cl-4-F-phenyl 5-diyl 198 —CH₂— pyridin-3, bond2-Cl-5-F-phenyl 5-diyl 199 —CH₂— pyridin-3, bond 3-Cl-4-F-phenyl 5-diyl200 —CH₂— pyridin-3, bond 3-Cl-5-F-phenyl 5-diyl 201 —CH₂— pyridin-3,bond 4-Cl-2-F-phenyl 5-diyl 202 —CH₂— pyridin-3, bond 4-Cl-3-F-phenyl5-diyl 203 —CH₂— pyridin-3, bond 2,3-diMeO-phenyl 5-diyl 204 —CH₂—pyridin-3, bond 2,4-diMeO-phenyl 5-diyl 205 —CH₂— pyridin-3, bond2,5-diMeO-phenyl 5-diyl 206 —CH₂— pyridin-3, bond 2,6-diMeO-phenyl5-diyl 207 —CH₂— pyridin-3, bond 3,4-diMeO-phenyl 5-diyl 208 —CH₂—pyridin-3, bond 3,5-diMeO-phenyl 5-diyl 209 —CH₂— pyridin-3, bondcyclopropyl 5-diyl 210 —CH₂— pyridin-3, bond cyclobutyl 5-diyl 211 —CH₂—pyridin-3, bond cyclopentyl 5-diyl 212 —CH₂— pyridin-3, bond cyclohexyl5-diyl 213 —CH₂— pyridin-3, bond 2-furanyl 5-diyl 214 —CH₂— pyridin-3,bond 2-thienyl 5-diyl 215 —CH₂— pyridin-3, bond 2-imidazolyl 5-diyl 216—CH₂— pyridin-3, bond 2-pyridyl 5-diyl 217 —CH₂— pyridin-3, bond3-pyridyl 5-diyl 218 —CH₂— pyridin-3, bond 4-pyridyl 5-diyl 219 —CH₂—pyridin-3, bond N-morpholinyl 5-diyl 220 —CH₂— pyridin-3, bondN-piperidinyl 5-diyl 221 —CH₂— pyridin-3, bond 3-Me-2-pyridyl 5-diyl 222—CH₂— pyridin-3, bond 4-Me-2-pyridyl 5-diyl 223 —CH₂— pyridin-3, bond1-indolyl 5-diyl 224 —CH₂— pyridin-3, bond 2-benzothienyl 5-diyl 225—CH₂— pyridin-3, bond 2-benzofuranyl 5-diyl 226 —CH₂— pyridin-3, bond1-benzimidazole 5-diyl 227 —CH₂— pyridin-3, bond 2-naphthyl 5-diyl 228—CH₂— pyridin-2, bond phenyl 6-diyl 229 —CH₂— pyridin-2, bond 3,3-6-diyl diphenylmethyl 230 —CH₂— pyridin-2, bond 2-F-phenyl 6-diyl 231—CH₂— pyridin-2, bond 3-F-phenyl 6-diyl 232 —CH₂— pyridin-2, bond4-F-phenyl 6-diyl 233 —CH₂— pyridin-2, bond 2-Cl-phenyl 6-diyl 234 —CH₂—pyridin-2, bond 3-Cl-phenyl 6-diyl 235 —CH₂— pyridin-2, bond 4-Cl-phenyl6-diyl 236 —CH₂— pyridin-2, bond 2-Me-phenyl 6-diyl 237 —CH₂— pyridin-2,bond 3-Me-phenyl 6-diyl 238 —CH₂— pyridin-2, bond 4-Me-phenyl 6-diyl 239—CH₂— pyridin-2, bond 2-MeO-phenyl 6-diyl 240 —CH₂— pyridin-2, bond3-MeO-phenyl 6-diyl 241 —CH₂— pyridin-2, bond 4-MeO-phenyl 6-diyl 242—CH₂— pyridin-2, bond 2-MeS-phenyl 6-diyl 243 —CH₂— pyridin-2, bond3-MeS-phenyl 6-diyl 244 —CH₂— pyridin-2, bond 4-MeS-phenyl 6-diyl 245—CH₂— pyridin-2, bond 2-F₃C-phenyl 6-diyl 246 —CH₂— pyridin-2, bond3-F₃C-phenyl 6-diyl 247 —CH₂— pyridin-2, bond 4-F₃C-phenyl 6-diyl 248—CH₂— pyridin-2, bond 2,3-diF-phenyl 6-diyl 249 —CH₂— pyridin-2, bond2,4-diF-phenyl 6-diyl 250 —CH₂— pyridin-2, bond 2,5-diF-phenyl 6-diyl251 —CH₂— pyridin-2, bond 2,6-diF-phenyl 6-diyl 252 —CH₂— pyridin-2,bond 3,4-diF-phenyl 6-diyl 253 —CH₂— pyridin-2, bond 3,5-diF-phenyl6-diyl 254 —CH₂— pyridin-2, bond 2,3-diCl-phenyl 6-diyl 255 —CH₂—pyridin-2, bond 2,4-diCl-phenyl 6-diyl 256 —CH₂— pyridin-2, bond2,5-diCl-phenyl 6-diyl 257 —CH₂— pyridin-2, bond 2,6-diCl-phenyl 6-diyl258 —CH₂— pyridin-2, bond 3,4-diCl-phenyl 6-diyl 259 —CH₂— pyridin-2,bond 3,5-diCl-phenyl 6-diyl 260 —CH₂— pyridin-2, bond 2-Cl-3-F-phenyl6-diyl 261 —CH₂— pyridin-2, bond 2-Cl-4-F-phenyl 6-diyl 262 —CH₂—pyridin-2, bond 2-Cl-5-F-phenyl 6-diyl 263 —CH₂— pyridin-2, bond3-Cl-4-F-phenyl 6-diyl 264 —CH₂— pyridin-2, bond 3-Cl-5-F-phenyl 6-diyl265 —CH₂— pyridin-2, bond 4-Cl-2-F-phenyl 6-diyl 266 —CH₂— pyridin-2,bond 4-Cl-3-F-phenyl 6-diyl 267 —CH₂— pyridin-2, bond 2,3-diMeO-phenyl6-diyl 268 —CH₂— pyridin-2, bond 2,4-diMeO-phenyl 6-diyl 269 —CH₂—pyridin-2, bond 2,5-diMeO-phenyl 6-diyl 270 —CH₂— pyridin-2, bond2,6-diMeO-phenyl 6-diyl 271 —CH₂— pyridin-2, bond 3,4-diMeO-phenyl6-diyl 272 —CH₂— pyridin-2, bond 3,5-diMeO-phenyl 6-diyl 273 —CH₂—pyridin-2, bond cyclopropyl 6-diyl 274 —CH₂— pyridin-2, bond cyclobutyl6-diyl 275 —CH₂— pyridin-2, bond cyclopentyl 6-diyl 276 —CH₂— pyridin-2,bond cyclohexyl 6-diyl 277 —CH₂— pyridin-2, bond 2-furanyl 6-diyl 278—CH₂— pyridin-2, bond 2-thienyl 6-diyl 279 —CH₂— pyridin-2, bond2-imidazolyl 6-diyl 280 —CH₂— pyridin-2, bond 2-pyridyl 6-diyl 281 —CH₂—pyridin-2, bond 3-pyridyl 6-diyl 282 —CH₂— pyridin-2, bond 4-pyridyl6-diyl 283 —CH₂— pyridin-2, bond N-morpholinyl 6-diyl 284 —CH₂—pyridin-2, bond N-piperidinyl 6-diyl 285 —CH₂— pyridin-2, bond3-Me-2-pyridyl 6-diyl 286 —CH₂— pyridin-2, bond 4-Me-2-pyridyl 6-diyl287 —CH₂— pyridin-2, bond 1-indolyl 6-diyl 288 —CH₂— pyridin-2, bond2-benzothienyl 6-diyl 289 —CH₂— pyridin-2, bond 2-benzofuranyl 6-diyl290 —CH₂— pyridin-2, bond 1-benzimidazole 6-diyl 291 —CH₂— pyridin-2,bond 2-naphthyl 6-diyl 292 —CH₂— pyridin-2, bond phenyl 4-diyl 293 —CH₂—pyridin-2, bond 3,3- 4-diyl diphenylmethyl 294 —CH₂— pyridin-2, bond2-F-phenyl 4-diyl 295 —CH₂— pyridin-2, bond 3-F-phenyl 4-diyl 296 —CH₂—pyridin-2, bond 4-F-phenyl 4-diyl 297 —CH₂— pyridin-2, bond 2-Cl-phenyl4-diyl 298 —CH₂— pyridin-2, bond 3-Cl-phenyl 4-diyl 299 —CH₂— pyridin-2,bond 4-Cl-phenyl 4-diyl 300 —CH₂— pyridin-2, bond 2-Me-phenyl 4-diyl 301—CH₂— pyridin-2, bond 3-Me-phenyl 4-diyl 302 —CH₂— pyridin-2, bond4-Me-phenyl 4-diyl 303 —CH₂— pyridin-2, bond 2-MeO-phenyl 4-diyl 304—CH₂— pyridin-2, bond 3-MeO-phenyl 4-diyl 305 —CH₂— pyridin-2, bond4-MeO-phenyl 4-diyl 306 —CH₂— pyridin-2, bond 2-MeS-phenyl 4-diyl 307—CH₂— pyridin-2, bond 3-MeS-phenyl 4-diyl 308 —CH₂— pyridin-2, bond4-MeS-phenyl 4-diyl 309 —CH₂— pyridin-2, bond 2-F₃C-phenyl 4-diyl 310—CH₂— pyridin-2, bond 3-F₃C-phenyl 4-diyl 311 —CH₂— pyridin-2, bond4-F₃C-phenyl 4-diyl 312 —CH₂— pyridin-2, bond 2,3-diF-phenyl 4-diyl 313—CH₂— pyridin-2, bond 2,4-diF-phenyl 4-diyl 314 —CH₂— pyridin-2, bond2,5-diF-phenyl 4-diyl 315 —CH₂— pyridin-2, bond 2,6-diF-phenyl 4-diyl316 —CH₂— pyridin-2, bond 3,4-diF-phenyl 4-diyl 317 —CH₂— pyridin-2,bond 3,5-diF-phenyl 4-diyl 318 —CH₂— pyridin-2, bond 2,3-diCl-phenyl4-diyl 319 —CH₂— pyridin-2, bond 2,4-diCl-phenyl 4-diyl 320 —CH₂—pyridin-2, bond 2,5-diCl-phenyl 4-diyl 321 —CH₂— pyridin-2, bond2,6-diCl-phenyl 4-diyl 322 —CH₂— pyridin-2, bond 3,4-diCl-phenyl 4-diyl323 —CH₂— pyridin-2, bond 3,5-diCl-phenyl 4-diyl 324 —CH₂— pyridin-2,bond 2-Cl-3-F-phenyl 4-diyl 325 —CH₂— pyridin-2, bond 2-Cl-4-F-phenyl4-diyl 326 —CH₂— pyridin-2, bond 2-Cl-5-F-phenyl 4-diyl 327 —CH₂—pyridin-2, bond 3-Cl-4-F-phenyl 4-diyl 328 —CH₂— pyridin-2, bond3-Cl-5-F-phenyl 4-diyl 329 —CH₂— pyridin-2, bond 4-Cl-2-F-phenyl 4-diyl330 —CH₂— pyridin-2, bond 4-Cl-3-F-phenyl 4-diyl 331 —CH₂— pyridin-2,bond 2,3-diMeO-phenyl 4-diyl 332 —CH₂— pyridin-2, bond 2,4-diMeO-phenyl4-diyl 333 —CH₂— pyridin-2, bond 2,5-diMeO-phenyl 4-diyl 334 —CH₂—pyridin-2, bond 2,6-diMeO-phenyl 4-diyl 335 —CH₂— pyridin-2, bond3,4-diMeO-phenyl 4-diyl 336 —CH₂— pyridin-2, bond 3,5-diMeO-phenyl4-diyl 337 —CH₂— pyridin-2, bond cyclopropyl 4-diyl 338 —CH₂— pyridin-2,bond cyclobutyl 4-diyl 339 —CH₂— pyridin-2, bond cyclopentyl 4-diyl 340—CH₂— pyridin-2, bond cyclohexyl 4-diyl 341 —CH₂— pyridin-2, bond2-furanyl 4-diyl 342 —CH₂— pyridin-2, bond 2-thienyl 4-diyl 343 —CH₂—pyridin-2, bond 2-imidazolyl 4-diyl 344 —CH₂— pyridin-2, bond 2-pyridyl4-diyl 345 —CH₂— pyridin-2, bond 3-pyridyl 4-diyl 346 —CH₂— pyridin-2,bond 4-pyridyl 4-diyl 347 —CH₂— pyridin-2, bond N-morpholinyl 4-diyl 348—CH₂— pyridin-2, bond N-piperidinyl 4-diyl 349 —CH₂— pyridin-2, bond3-Me-2-pyridyl 4-diyl 350 —CH₂— pyridin-2, bond 4-Me-2-pyridyl 4-diyl351 —CH₂— pyridin-2, bond 1-indolyl 4-diyl 352 —CH₂— pyridin-2, bond2-benzothienyl 4-diyl 353 —CH₂— pyridin-2, bond 2-benzofuranyl 4-diyl354 —CH₂— pyridin-2, bond 1-benzimidazole 4-diyl 355 —CH₂— pyridin-2,bond 2-naphthyl 4-diyl 356 —CH₂— pyridin-4, bond phenyl 2-diyl 357 —CH₂—pyridin-4, bond 3,3- 2-diyl diphenylmethyl 358 —CH₂— pyridin-4, bond2-F-phenyl 2-diyl 359 —CH₂— pyridin-4, bond 3-F-phenyl 2-diyl 360 —CH₂—pyridin-4, bond 4-F-phenyl 2-diyl 361 —CH₂— pyridin-4, bond 2-Cl-phenyl2-diyl 362 —CH₂— pyridin-4, bond 3-Cl-phenyl 2-diyl 363 —CH₂— pyridin-4,bond 4-Cl-phenyl 2-diyl 364 —CH₂— pyridin-4, bond 2-Me-phenyl 2-diyl 365—CH₂— pyridin-4, bond 3-Me-phenyl 2-diyl 366 —CH₂— pyridin-4, bond4-Me-phenyl 2-diyl 367 —CH₂— pyridin-4, bond 2-MeO-phenyl 2-diyl 368—CH₂— pyridin-4, bond 3-MeO-phenyl 2-diyl 369 —CH₂— pyridin-4, bond4-MeO-phenyl 2-diyl 370 —CH₂— pyridin-4, bond 2-MeS-phenyl 2-diyl 371—CH₂— pyridin-4, bond 3-MeS-phenyl 2-diyl 372 —CH₂— pyridin-4, bond4-MeS-phenyl 2-diyl 373 —CH₂— pyridin-4, bond 2-F₃C-phenyl 2-diyl 374—CH₂— pyridin-4, bond 3-F₃C-phenyl 2-diyl 375 —CH₂— pyridin-4, bond4-F₃C-phenyl 2-diyl 376 —CH₂— pyridin-4, bond 2,3-diF-phenyl 2-diyl 377—CH₂— pyridin-4, bond 2,4-diF-phenyl 2-diyl 378 —CH₂— pyridin-4, bond2,5-diF-phenyl 2-diyl 379 —CH₂— pyridin-4, bond 2,6-diF-phenyl 2-diyl380 —CH₂— pyridin-4, bond 3,4-diF-phenyl 2-diyl 381 —CH₂— pyridin-4,bond 3,5-diF-phenyl 2-diyl 382 —CH₂— pyridin-4, bond 2,3-diCl-phenyl2-diyl 383 —CH₂— pyridin-4, bond 2,4-diCl-phenyl 2-diyl 384 —CH₂—pyridin-4, bond 2,5-diCl-phenyl 2-diyl 385 —CH₂— pyridin-4, bond2,6-diCl-phenyl 2-diyl 386 —CH₂— pyridin-4, bond 3,4-diCl-phenyl 2-diyl387 —CH₂— pyridin-4, bond 3,5-diCl-phenyl 2-diyl 388 —CH₂— pyridin-4,bond 2-Cl-3-F-phenyl 2-diyl 389 —CH₂— pyridin-4, bond 2-Cl-4-F-phenyl2-diyl 390 —CH₂— pyridin-4, bond 2-Cl-5-F-phenyl 2-diyl 391 —CH₂—pyridin-4, bond 3-Cl-4-F-phenyl 2-diyl 392 —CH₂— pyridin-4, bond3-Cl-5-F-phenyl 2-diyl 393 —CH₂— pyridin-4, bond 4-Cl-2-F-phenyl 2-diyl394 —CH₂— pyridin-4, bond 4-Cl-3-F-phenyl 2-diyl 395 —CH₂— pyridin-4,bond 2,3-diMeO-phenyl 2-diyl 396 —CH₂— pyridin-4, bond 2,4-diMeO-phenyl2-diyl 397 —CH₂— pyridin-4, bond 2,5-diMeO-phenyl 2-diyl 398 —CH₂—pyridin-4, bond 2,6-diMeO-phenyl 2-diyl 399 —CH₂— pyridin-4, bond3,4-diMeO-phenyl 2-diyl 400 —CH₂— pyridin-4, bond 3,5-diMeO-phenyl2-diyl 401 —CH₂— pyridin-4, bond cyclopropyl 2-diyl 402 —CH₂— pyridin-4,bond cyclobutyl 2-diyl 403 —CH₂— pyridin-4, bond cyclopentyl 2-diyl 404—CH₂— pyridin-4, bond cyclohexyl 2-diyl 405 —CH₂— pyridin-4, bond2-furanyl 2-diyl 406 —CH₂— pyridin-4, bond 2-thienyl 2-diyl 407 —CH₂—pyridin-4, bond 2-imidazolyl 2-diyl 408 —CH₂— pyridin-4, bond 2-pyridyl2-diyl 409 —CH₂— pyridin-4, bond 3-pyridyl 2-diyl 410 —CH₂— pyridin-4,bond 4-pyridyl 2-diyl 411 —CH₂— pyridin-4, bond N-morpholinyl 2-diyl 412—CH₂— pyridin-4, bond N-piperidinyl 2-diyl 413 —CH₂— pyridin-4, bond3-Me-2-pyridyl 2-diyl 414 —CH₂— pyridin-4, bond 4-Me-2-pyridyl 2-diyl415 —CH₂— pyridin-4, bond 1-indolyl 2-diyl 416 —CH₂— pyridin-4, bond2-benzothienyl 2-diyl 417 —CH₂— pyridin-4, bond 2-benzofuranyl 2-diyl418 —CH₂— pyridin-4, bond 1-benzimidazole 2-diyl 419 —CH₂— pyridin-4,bond 2-naphthyl 2-diyl 420 —CH₂— piperidin- bond phenyl 1,3-diyl 421—CH₂— piperidin- bond 3,3- 1,3-diyl diphenylmethyl 422 —CH₂— piperidin-bond 2-F-phenyl 1,3-diyl 423 —CH₂— piperidin- bond 3-F-phenyl 1,3-diyl424 —CH₂— piperidin- bond 4-F-phenyl 1,3-diyl 425 —CH₂— piperidin- bond2-Cl-phenyl 1,3-diyl 426 —CH₂— piperidin- bond 3-Cl-phenyl 1,3-diyl 427—CH₂— piperidin- bond 4-Cl-phenyl 1,3-diyl 428 —CH₂— piperidin- bond2-Me-phenyl 1,3-diyl 429 —CH₂— piperidin- bond 3-Me-phenyl 1,3-diyl 430—CH₂— piperidin- bond 4-Me-phenyl 1,3-diyl 431 —CH₂— piperidin- bond2-MeO-phenyl 1,3-diyl 432 —CH₂— piperidin- bond 3-MeO-phenyl 1,3-diyl433 —CH₂— piperidin- bond 4-MeO-phenyl 1,3-diyl 434 —CH₂— piperidin-bond 2-MeS-phenyl 1,3-diyl 435 —CH₂— piperidin- bond 3-MeS-phenyl1,3-diyl 436 —CH₂— piperidin- bond 4-MeS-phenyl 1,3-diyl 437 —CH₂—piperidin- bond 2-F₃C-phenyl 1,3-diyl 438 —CH₂— piperidin- bond3-F₃C-phenyl 1,3-diyl 439 —CH₂— piperidin- bond 4-F₃C-phenyl 1,3-diyl440 —CH₂— piperidin- bond 2,3-diF-phenyl 1,3-diyl 441 —CH₂— piperidin-bond 2,4-diF-phenyl 1,3-diyl 442 —CH₂— piperidin- bond 2,5-diF-phenyl1,3-diyl 443 —CH₂— piperidin- bond 2,6-diF-phenyl 1,3-diyl 444 —CH₂—piperidin- bond 3,4-diF-phenyl 1,3-diyl 445 —CH₂— piperidin- bond3,5-diF-phenyl 1,3-diyl 446 —CH₂— piperidin- bond 2,3-diCl-phenyl1,3-diyl 447 —CH₂— piperidin- bond 2,4-diCl-phenyl 1,3-diyl 448 —CH₂—piperidin- bond 2,5-diCl-phenyl 1,3-diyl 449 —CH₂— piperidin- bond2,6-diCl-phenyl 1,3-diyl 450 —CH₂— piperidin- bond 3,4-diCl-phenyl1,3-diyl 451 —CH₂— piperidin- bond 3,5-diCl-phenyl 1,3-diyl 452 —CH₂—piperidin- bond 2-Cl-3-F-phenyl 1,3-diyl 453 —CH₂— piperidin- bond2-Cl-4-F-phenyl 1,3-diyl 454 —CH₂— piperidin- bond 2-Cl-5-F-phenyl1,3-diyl 455 —CH₂— piperidin- bond 3-Cl-4-F-phenyl 1,3-diyl 456 —CH₂—piperidin- bond 3-Cl-5-F-phenyl 1,3-diyl 457 —CH₂— piperidin- bond4-Cl-2-F-phenyl 1,3-diyl 458 —CH₂— piperidin- bond 4-Cl-3-F-phenyl1,3-diyl 459 —CH₂— piperidin- bond 2,3-diMeO-phenyl 1,3-diyl 460 —CH₂—piperidin- bond 2,4-diMeO-phenyl 1,3-diyl 461 —CH₂— piperidin- bond2,5-diMeO-phenyl 1,3-diyl 462 —CH₂— piperidin- bond 2,6-diMeO-phenyl1,3-diyl 463 —CH₂— piperidin- bond 3,4-diMeO-phenyl 1,3-diyl 464 —CH₂—piperidin- bond 3,5-diMeO-phenyl 1,3-diyl 465 —CH₂— piperidin- bondcyclopropyl 1,3-diyl 466 —CH₂— piperidin- bond cyclobutyl 1,3-diyl 467—CH₂— piperidin- bond cyclopentyl 1,3-diyl 468 —CH₂— piperidin- bondcyclohexyl 1,3-diyl 469 —CH₂— piperidin- bond 2-furanyl 1,3-diyl 470—CH₂— piperidin- bond 2-thienyl 1,3-diyl 471 —CH₂— piperidin- bond2-imidazolyl 1,3-diyl 472 —CH₂— piperidin- bond 2-pyridyl 1,3-diyl 473—CH₂— piperidin- bond 3-pyridyl 1,3-diyl 474 —CH₂— piperidin- bond4-pyridyl 1,3-diyl 475 —CH₂— piperidin- bond N-morpholinyl 1,3-diyl 476—CH₂— piperidin- bond N-piperidinyl 1,3-diyl 477 —CH₂— piperidin- bond3-Me-2-pyridyl 1,3-diyl 478 —CH₂— piperidin- bond 4-Me-2-pyridyl1,3-diyl 479 —CH₂— piperidin- bond 1-indolyl 1,3-diyl 480 —CH₂—piperidin- bond 2-benzothienyl 1,3-diyl 481 —CH₂— piperidin- bond2-benzofuranyl 1,3-diyl 482 —CH₂— piperidin- bond 1-benzimidazole1,3-diyl 483 —CH₂— piperidin- bond 2-naphthyl 1,3-diyl 484 —CH₂—piperidin- bond phenyl 3,1-diyl 485 —CH₂— piperidin- bond 3,3- 3,1-diyldiphenylmethyl 486 —CH₂— piperidin- bond 2-F-phenyl 3,1-diyl 487 —CH₂—piperidin- bond 3-F-phenyl 3,1-diyl 488 —CH₂— piperidin- bond 4-F-phenyl3,1-diyl 489 —CH₂— piperidin- bond 2-Cl-phenyl 3,1-diyl 490 —CH₂—piperidin- bond 3-Cl-phenyl 3,1-diyl 491 —CH₂— piperidin- bond4-Cl-phenyl 3,1-diyl 492 —CH₂— piperidin- bond 2-Me-phenyl 3,1-diyl 493—CH₂— piperidin- bond 3-Me-phenyl 3,1-diyl 494 —CH₂— piperidin- bond4-Me-phenyl 3,1-diyl 495 —CH₂— piperidin- bond 2-MeO-phenyl 3,1-diyl 496—CH₂— piperidin- bond 3-MeO-phenyl 3,1-diyl 497 —CH₂— piperidin- bond4-MeO-phenyl 3,1-diyl 498 —CH₂— piperidin- bond 2-MeS-phenyl 3,1-diyl499 —CH₂— piperidin- bond 3-MeS-phenyl 3,1-diyl 500 —CH₂— piperidin-bond 4-MeS-phenyl 3,1-diyl 501 —CH₂— piperidin- bond 2-F₃C-phenyl3,1-diyl 502 —CH₂— piperidin- bond 3-F₃C-phenyl 3,1-diyl 503 —CH₂—piperidin- bond 4-F₃C-phenyl 3,1-diyl 504 —CH₂— piperidin- bond2,3-diF-phenyl 3,1-diyl 505 —CH₂— piperidin- bond 2,4-diF-phenyl3,1-diyl 506 —CH₂— piperidin- bond 2,5-diF-phenyl 3,1-diyl 507 —CH₂—piperidin- bond 2,6-diF-phenyl 3,1-diyl 508 —CH₂— piperidin- bond3,4-diF-phenyl 3,1-diyl 509 —CH₂— piperidin- bond 3,5-diF-phenyl3,1-diyl 510 —CH₂— piperidin- bond 2,3-diCl-phenyl 3,1-diyl 511 —CH₂—piperidin- bond 2,4-diCl-phenyl 3,1-diyl 512 —CH₂— piperidin- bond2,5-diCl-phenyl 3,1-diyl 513 —CH₂— piperidin- bond 2,6-diCl-phenyl3,1-diyl 514 —CH₂— piperidin- bond 3,4-diCl-phenyl 3,1-diyl 515 —CH₂—piperidin- bond 3,5-diCl-phenyl 3,1-diyl 516 —CH₂— piperidin- bond2-Cl-3-F-phenyl 3,1-diyl 517 —CH₂— piperidin- bond 2-Cl-4-F-phenyl3,1-diyl 518 —CH₂— piperidin- bond 2-Cl-5-F-phenyl 3,1-diyl 519 —CH₂—piperidin- bond 3-Cl-4-F-phenyl 3,1-diyl 520 —CH₂— piperidin- bond3-Cl-5-F-phenyl 3,1-diyl 521 —CH₂— piperidin- bond 4-Cl-2-F-phenyl3,1-diyl 522 —CH₂— piperidin- bond 4-Cl-3-F-phenyl 3,1-diyl 523 —CH₂—piperidin- bond 2,3-diMeO-phenyl 3,1-diyl 524 —CH₂— piperidin- bond2,4-diMeO-phenyl 3,1-diyl 525 —CH₂— piperidin- bond 2,5-diMeO-phenyl3,1-diyl 526 —CH₂— piperidin- bond 2,6-diMeO-phenyl 3,1-diyl 527 —CH₂—piperidin- bond 3,4-diMeO-phenyl 3,1-diyl 528 —CH₂— piperidin- bond3,5-diMeO-phenyl 3,1-diyl 529 —CH₂— piperidin- bond cyclopropyl 3,1-diyl530 —CH₂— piperidin- bond cyclobutyl 3,1-diyl 531 —CH₂— piperidin- bondcyclopentyl 3,1-diyl 532 —CH₂— piperidin- bond cyclohexyl 3,1-diyl 533—CH₂— piperidin- bond 2-furanyl 3,1-diyl 534 —CH₂— piperidin- bond2-thienyl 3,1-diyl 535 —CH₂— piperidin- bond 2-imidazolyl 3,1-diyl 536—CH₂— piperidin- bond 2-pyridyl 3,1-diyl 537 —CH₂— piperidin- bond3-pyridyl 3,1-diyl 538 —CH₂— piperidin- bond 4-pyridyl 3,1-diyl 539—CH₂— piperidin- bond N-morpholinyl 3,1-diyl 540 —CH₂— piperidin- bondN-piperidinyl 3,1-diyl 541 —CH₂— piperidin- bond 3-Me-2-pyridyl 3,1-diyl542 —CH₂— piperidin- bond 4-Me-2-pyridyl 3,1-diyl 543 —CH₂— piperidin-bond 1-indolyl 3,1-diyl 544 —CH₂— piperidin- bond 2-benzothienyl3,1-diyl 545 —CH₂— piperidin- bond 2-benzofuranyl 3,1-diyl 546 —CH₂—piperidin- bond 1-benzimidazole 3,1-diyl 547 —CH₂— piperidin- bond2-naphthyl 3,1-diyl 548 —CH₂— cyclohex- bond phenyl 1,3-diyl 549 —CH₂—cyclohex- bond 3,3- 1,3-diyl diphenylmethyl 550 —CH₂— cyclohex- bond2-F-phenyl 1,3-diyl 551 —CH₂— cyclohex- bond 3-F-phenyl 1,3-diyl 552—CH₂— cyclohex- bond 4-F-phenyl 1,3-diyl 553 —CH₂— cyclohex- bond2-Cl-phenyl 1,3-diyl 554 —CH₂— cyclohex- bond 3-Cl-phenyl 1,3-diyl 555—CH₂— cyclohex- bond 4-Cl-phenyl 1,3-diyl 556 —CH₂— cyclohex- bond2-Me-phenyl 1,3-diyl 557 —CH₂— cyclohex- bond 3-Me-phenyl 1,3-diyl 558—CH₂— cyclohex- bond 4-Me-phenyl 1,3-diyl 559 —CH₂— cyclohex- bond2-MeO-phenyl 1,3-diyl 560 —CH₂— cyclohex- bond 3-MeO-phenyl 1,3-diyl 561—CH₂— cyclohex- bond 4-MeO-phenyl 1,3-diyl 562 —CH₂— cyclohex- bond2-MeS-phenyl 1,3-diyl 563 —CH₂— cyclohex- bond 3-MeS-phenyl 1,3-diyl 564—CH₂— cyclohex- bond 4-MeS-phenyl 1,3-diyl 565 —CH₂— cyclohex- bond2-F₃C-phenyl 1,3-diyl 566 —CH₂— cyclohex- bond 3-F₃C-phenyl 1,3-diyl 567—CH₂— cyclohex- bond 4-F₃C-phenyl 1,3-diyl 568 —CH₂— cyclohex- bond2,3-diF-phenyl 1,3-diyl 569 —CH₂— cyclohex- bond 2,4-diF-phenyl 1,3-diyl570 —CH₂— cyclohex- bond 2,5-diF-phenyl 1,3-diyl 571 —CH₂— cyclohex-bond 2,6-diF-phenyl 1,3-diyl 572 —CH₂— cyclohex- bond 3,4-diF-phenyl1,3-diyl 573 —CH₂— cyclohex- bond 3,5-diF-phenyl 1,3-diyl 574 —CH₂—cyclohex- bond 2,3-diCl-phenyl 1,3-diyl 575 —CH₂— cyclohex- bond2,4-diCl-phenyl 1,3-diyl 576 —CH₂— cyclohex- bond 2,5-diCl-phenyl1,3-diyl 577 —CH₂— cyclohex- bond 2,6-diCl-phenyl 1,3-diyl 578 —CH₂—cyclohex- bond 3,4-diCl-phenyl 1,3-diyl 579 —CH₂— cyclohex- bond3,5-diCl-phenyl 1,3-diyl 580 —CH₂— cyclohex- bond 2-Cl-3-F-phenyl1,3-diyl 581 —CH₂— cyclohex- bond 2-Cl-4-F-phenyl 1,3-diyl 582 —CH₂—cyclohex- bond 2-Cl-5-F-phenyl 1,3-diyl 583 —CH₂— cyclohex- bond3-Cl-4-F-phenyl 1,3-diyl 584 —CH₂— cyclohex- bond 3-Cl-5-F-phenyl1,3-diyl 585 —CH₂— cyclohex- bond 4-Cl-2-F-phenyl 1,3-diyl 586 —CH₂—cyclohex- bond 4-Cl-3-F-phenyl 1,3-diyl 587 —CH₂— cyclohex- bond2,3-diMeO-phenyl 1,3-diyl 588 —CH₂— cyclohex- bond 2,4-diMeO-phenyl1,3-diyl 589 —CH₂— cyclohex- bond 2,5-diMeO-phenyl 1,3-diyl 590 —CH₂—cyclohex- bond 2,6-diMeO-phenyl 1,3-diyl 591 —CH₂— cyclohex- bond3,4-diMeO-phenyl 1,3-diyl 592 —CH₂— cyclohex- bond 3,5-diMeO-phenyl1,3-diyl 593 —CH₂— cyclohex- bond cyclopropyl 1,3-diyl 594 —CH₂—cyclohex- bond cyclobutyl 1,3-diyl 595 —CH₂— cyclohex- bond cyclopentyl1,3-diyl 596 —CH₂— cyclohex- bond cyclohexyl 1,3-diyl 597 —CH₂—cyclohex- bond 2-furanyl 1,3-diyl 598 —CH₂— cyclohex- bond 2-thienyl1,3-diyl 599 —CH₂— cyclohex- bond 2-imidazolyl 1,3-diyl 600 —CH₂—cyclohex- bond 2-pyridyl 1,3-diyl 601 —CH₂— cyclohex- bond 3-pyridyl1,3-diyl 602 —CH₂— cyclohex- bond 4-pyridyl 1,3-diyl 603 —CH₂— cyclohex-bond N-morpholinyl 1,3-diyl 604 —CH₂— cyclohex- bond N-piperidinyl1,3-diyl 605 —CH₂— cyclohex- bond 3-Me-2-pyridyl 1,3-diyl 606 —CH₂—cyclohex- bond 4-Me-2-pyridyl 1,3-diyl 607 —CH₂— cyclohex- bond1-indolyl 1,3-diyl 608 —CH₂— cyclohex- bond 2-benzothienyl 1,3-diyl 609—CH₂— cyclohex- bond 2-benzofuranyl 1,3-diyl 610 —CH₂— cyclohex- bond1-benzimidazole 1,3-diyl 611 —CH₂— cyclohex- bond 2-naphthyl 1,3-diyl612 —CH₂— cyclopropan- bond phenyl 1,2-diyl 613 —CH₂— cyclopropan- bond3,3- 1,2-diyl diphenylmethyl 614 —CH₂— cyclopropan- bond 2-F-phenyl1,2-diyl 615 —CH₂— cyclopropan- bond 3-F-phenyl 1,2-diyl 616 —CH₂—cyclopropan- bond 4-F-phenyl 1,2-diyl 617 —CH₂— cyclopropan- bond2-Cl-phenyl 1,2-diyl 618 —CH₂— cyclopropan- bond 3-Cl-phenyl 1,2-diyl619 —CH₂— cyclopropan- bond 4-Cl-phenyl 1,2-diyl 620 —CH₂— cyclopropan-bond 2-Me-phenyl 1,2-diyl 621 —CH₂— cyclopropan- bond 3-Me-phenyl1,2-diyl 622 —CH₂— cyclopropan- bond 4-Me-phenyl 1,2-diyl 623 —CH₂—cyclopropan- bond 2-MeO-phenyl 1,2-diyl 624 —CH₂— cyclopropan- bond3-MeO-phenyl 1,2-diyl 625 —CH₂— cyclopropan- bond 4-MeO-phenyl 1,2-diyl626 —CH₂— cyclopropan- bond 2-MeS-phenyl 1,2-diyl 627 —CH₂— cyclopropan-bond 3-MeS-phenyl 1,2-diyl 628 —CH₂— cyclopropan- bond 4-MeS-phenyl1,2-diyl 629 —CH₂— cyclopropan- bond 2-F₃C-phenyl 1,2-diyl 630 —CH₂—cyclopropan- bond 3-F₃C-phenyl 1,2-diyl 631 —CH₂— cyclopropan- bond4-F₃C-phenyl 1,2-diyl 632 —CH₂— cyclopropan- bond 2,3-diF-phenyl1,2-diyl 633 —CH₂— cyclopropan- bond 2,4-diF-phenyl 1,2-diyl 634 —CH₂—cyclopropan- bond 2,5-diF-phenyl 1,2-diyl 635 —CH₂— cyclopropan- bond2,6-diF-phenyl 1,2-diyl 636 —CH₂— cyclopropan- bond 3,4-diF-phenyl1,2-diyl 637 —CH₂— cyclopropan- bond 3,5-diF-phenyl 1,2-diyl 638 —CH₂—cyclopropan- bond 2,3-diCl-phenyl 1,2-diyl 639 —CH₂— cyclopropan- bond2,4-diCl-phenyl 1,2-diyl 640 —CH₂— cyclopropan- bond 2,5-diCl-phenyl1,2-diyl 641 —CH₂— cyclopropan- bond 2,6-diCl-phenyl 1,2-diyl 642 —CH₂—cyclopropan- bond 3,4-diCl-phenyl 1,2-diyl 643 —CH₂— cyclopropan- bond3,5-diCl-phenyl 1,2-diyl 644 —CH₂— cyclopropan- bond 2-Cl-3-F-phenyl1,2-diyl 645 —CH₂— cyclopropan- bond 2-Cl-4-F-phenyl 1,2-diyl 646 —CH₂—cyclopropan- bond 2-Cl-5-F-phenyl 1,2-diyl 647 —CH₂— cyclopropan- bond3-Cl-4-F-phenyl 1,2-diyl 648 —CH₂— cyclopropan- bond 3-Cl-5-F-phenyl1,2-diyl 649 —CH₂— cyclopropan- bond 4-Cl-2-F-phenyl 1,2-diyl 650 —CH₂—cyclopropan- bond 4-Cl-3-F-phenyl 1,2-diyl 651 —CH₂— cyclopropan- bond2,3-diMeO-phenyl 1,2-diyl 652 —CH₂— cyclopropan- bond 2,4-diMeO-phenyl1,2-diyl 653 —CH₂— cyclopropan- bond 2,5-diMeO-phenyl 1,2-diyl 654 —CH₂—cyclopropan- bond 2,6-diMeO-phenyl 1,2-diyl 655 —CH₂— cyclopropan- bond3,4-diMeO-phenyl 1,2-diyl 656 —CH₂— cyclopropan- bond 3,5-diMeO-phenyl1,2-diyl 657 —CH₂— cyclopropan- bond cyclopropyl 1,2-diyl 658 —CH₂—cyclopropan- bond cyclobutyl 1,2-diyl 659 —CH₂— cyclopropan- bondcyclopentyl 1,2-diyl 660 —CH₂— cyclopropan- bond cyclohexyl 1,2-diyl 661—CH₂— cyclopropan- bond 2-furanyl 1,2-diyl 662 —CH₂— cyclopropan- bond2-thienyl 1,2-diyl 663 —CH₂— cyclopropan- bond 2-imidazolyl 1,2-diyl 664—CH₂— cyclopropan- bond 2-pyridyl 1,2-diyl 665 —CH₂— cyclopropan- bond3-pyridyl 1,2-diyl 666 —CH₂— cyclopropan- bond 4-pyridyl 1,2-diyl 667—CH₂— cyclopropan- bond N-morpholinyl 1,2-diyl 668 —CH₂— cyclopropan-bond N-piperidinyl 1,2-diyl 669 —CH₂— cyclopropan- bond 3-Me-2-pyridyl1,2-diyl 670 —CH₂— cyclopropan- bond 4-Me-2-pyridyl 1,2-diyl 671 —CH₂—cyclopropan- bond 1-indolyl 1,2-diyl 672 —CH₂— cyclopropan- bond2-benzothienyl 1,2-diyl 673 —CH₂— cyclopropan- bond 2-benzofuranyl1,2-diyl 674 —CH₂— cyclopropan- bond 1-benzimidazole 1,2-diyl 675 —CH₂—cyclopropan- bond 2-naphthyl 1,2-diyl 676 —CH₂— cyclopentan- bond phenyl1,3-diyl 677 —CH₂— cyclopentan- bond 3,3- 1,3-diyl diphenylmethyl 678—CH₂— cyclopentan- bond 2-F-phenyl 1,3-diyl 679 —CH₂— cyclopentan- bond3-F-phenyl 1,3-diyl 680 —CH₂— cyclopentan- bond 4-F-phenyl 1,3-diyl 681—CH₂— cyclopentan- bond 2-Cl-phenyl 1,3-diyl 682 —CH₂— cyclopentan- bond3-Cl-phenyl 1,3-diyl 683 —CH₂— cyclopentan- bond 4-Cl-phenyl 1,3-diyl684 —CH₂— cyclopentan- bond 2-Me-phenyl 1,3-diyl 685 —CH₂— cyclopentan-bond 3-Me-phenyl 1,3-diyl 686 —CH₂— cyclopentan- bond 4-Me-phenyl1,3-diyl 687 —CH₂— cyclopentan- bond 2-MeO-phenyl 1,3-diyl 688 —CH₂—cyclopentan- bond 3-MeO-phenyl 1,3-diyl 689 —CH₂— cyclopentan- bond4-MeO-phenyl 1,3-diyl 690 —CH₂— cyclopentan- bond 2-MeS-phenyl 1,3-diyl691 —CH₂— cyclopentan- bond 3-MeS-phenyl 1,3-diyl 692 —CH₂— cyclopentan-bond 4-MeS-phenyl 1,3-diyl 693 —CH₂— cyclopentan- bond 2-F₃C-phenyl1,3-diyl 694 —CH₂— cyclopentan- bond 3-F₃C-phenyl 1,3-diyl 695 —CH₂—cyclopentan- bond 4-F₃C-phenyl 1,3-diyl 696 —CH₂— cyclopentan- bond2,3-diF-phenyl 1,3-diyl 697 —CH₂— cyclopentan- bond 2,4-diF-phenyl1,3-diyl 698 —CH₂— cyclopentan- bond 2,5-diF-phenyl 1,3-diyl 699 —CH₂—cyclopentan- bond 2,6-diF-phenyl 1,3-diyl 700 —CH₂— cyclopentan- bond3,4-diF-phenyl 1,3-diyl 701 —CH₂— cyclopentan- bond 3,5-diF-phenyl1,3-diyl 702 —CH₂— cyclopentan- bond 2,3-diCl-phenyl 1,3-diyl 703 —CH₂—cyclopentan- bond 2,4-diCl-phenyl 1,3-diyl 704 —CH₂— cyclopentan- bond2,5-diCl-phenyl 1,3-diyl 705 —CH₂— cyclopentan- bond 2,6-diCl-phenyl1,3-diyl 706 —CH₂— cyclopentan- bond 3,4-diCl-phenyl 1,3-diyl 707 —CH₂—cyclopentan- bond 3,5-diCl-phenyl 1,3-diyl 708 —CH₂— cyclopentan- bond2-Cl-3-F-phenyl 1,3-diyl 709 —CH₂— cyclopentan- bond 2-Cl-4-F-phenyl1,3-diyl 710 —CH₂— cyclopentan- bond 2-Cl-5-F-phenyl 1,3-diyl 711 —CH₂—cyclopentan- bond 3-Cl-4-F-phenyl 1,3-diyl 712 —CH₂— cyclopentan- bond3-Cl-5-F-phenyl 1,3-diyl 713 —CH₂— cyclopentan- bond 4-Cl-2-F-phenyl1,3-diyl 714 —CH₂— cyclopentan- bond 4-Cl-3-F-phenyl 1,3-diyl 715 —CH₂—cyclopentan- bond 2,3-diMeO-phenyl 1,3-diyl 716 —CH₂— cyclopentan- bond2,4-diMeO-phenyl 1,3-diyl 717 —CH₂— cyclopentan- bond 2,5-diMeO-phenyl1,3-diyl 718 —CH₂— cyclopentan- bond 2,6-diMeO-phenyl 1,3-diyl 719 —CH₂—cyclopentan- bond 3,4-diMeO-phenyl 1,3-diyl 720 —CH₂— cyclopentan- bond3,5-diMeO-phenyl 1,3-diyl 721 —CH₂— cyclopentan- bond cyclopropyl1,3-diyl 722 —CH₂— cyclopentan- bond cyclobutyl 1,3-diyl 723 —CH₂—cyclopentan- bond cyclopentyl 1,3-diyl 724 —CH₂— cyclopentan- bondcyclohexyl 1,3-diyl 725 —CH₂— cyclopentan- bond 2-furanyl 1,3-diyl 726—CH₂— cyclopentan- bond 2-thienyl 1,3-diyl 727 —CH₂— cyclopentan- bond2-imidazolyl 1,3-diyl 728 —CH₂— cyclopentan- bond 2-pyridyl 1,3-diyl 729—CH₂— cyclopentan- bond 3-pyridyl 1,3-diyl 730 —CH₂— cyclopentan- bond4-pyridyl 1,3-diyl 731 —CH₂— cyclopentan- bond N-morpholinyl 1,3-diyl732 —CH₂— cyclopentan- bond N-piperidinyl 1,3-diyl 733 —CH₂—cyclopentan- bond 3-Me-2-pyridyl 1,3-diyl 734 —CH₂— cyclopentan- bond4-Me-2-pyridyl 1,3-diyl 735 —CH₂— cyclopentan- bond 1-indolyl 1,3-diyl736 —CH₂— cyclopentan- bond 2-benzothienyl 1,3-diyl 737 —CH₂—cyclopentan- bond 2-benzofuranyl 1,3-diyl 738 —CH₂— cyclopentan- bond1-benzimidazole 1,3-diyl 739 —CH₂— cyclopentan- bond 2-naphthyl 1,3-diyl740 —CH₂— phen-1,3-diyl —O— phenyl 741 —CH₂— phen-1,3-diyl —O— 3,3-diphenylmethyl 742 —CH₂— phen-1,3-diyl —O— 2-F-phenyl 743 —CH₂—phen-1,3-diyl —O— 3-F-phenyl 744 —CH₂— phen-1,3-diyl —O— 4-F-phenyl 745—CH₂— phen-1,3-diyl —O— 2-Cl-phenyl 746 —CH₂— phen-1,3-diyl —O—3-Cl-phenyl 747 —CH₂— phen-1,3-diyl —O— 4-Cl-phenyl 748 —CH₂—phen-1,3-diyl —O— 2-Me-phenyl 749 —CH₂— phen-1,3-diyl —O— 3-Me-phenyl750 —CH₂— phen-1,3-diyl —O— 4-Me-phenyl 751 —CH₂— phen-1,3-diyl —O—2-MeO-phenyl 752 —CH₂— phen-1,3-diyl —O— 3-MeO-phenyl 753 —CH₂—phen-1,3-diyl —O— 4-MeO-phenyl 754 —CH₂— phen-1,3-diyl —O— 2-MeS-phenyl755 —CH₂— phen-1,3-diyl —O— 3-MeS-phenyl 756 —CH₂— phen-1,3-diyl —O—4-MeS-phenyl 757 —CH₂— phen-1,3-diyl —O— 2-F₃C-phenyl 758 —CH₂—phen-1,3-diyl —O— 3-F₃C-phenyl 759 —CH₂— phen-1,3-diyl —O— 4-F₃C-phenyl760 —CH₂— phen-1,3-diyl —O— 2,3-diF-phenyl 761 —CH₂— phen-1,3-diyl —O—2,4-diF-phenyl 762 —CH₂— phen-1,3-diyl —O— 2,5-diF-phenyl 763 —CH₂—phen-1,3-diyl —O— 2,6-diF-phenyl 764 —CH₂— phen-1,3-diyl —O—3,4-diF-phenyl 765 —CH₂— phen-1,3-diyl —O— 3,5-diF-phenyl 766 —CH₂—phen-1,3-diyl —O— 2,3-diCl-phenyl 767 —CH₂— phen-1,3-diyl —O—2,4-diCl-phenyl 768 —CH₂— phen-1,3-diyl —O— 2,5-diCl-phenyl 769 —CH₂—phen-1,3-diyl —O— 2,6-diCl-phenyl 770 —CH₂— phen-1,3-diyl —O—3,4-diCl-phenyl 771 —CH₂— phen-1,3-diyl —O— 3,5-diCl-phenyl 772 —CH₂—phen-1,3-diyl —O— 2-Cl-3-F-phenyl 773 —CH₂— phen-1,3-diyl —O—2-Cl-4-F-phenyl 774 —CH₂— phen-1,3-diyl —O— 2-Cl-5-F-phenyl 775 —CH₂—phen-1,3-diyl —O— 3-Cl-4-F-phenyl 776 —CH₂— phen-1,3-diyl —O—3-Cl-5-F-phenyl 777 —CH₂— phen-1,3-diyl —O— 4-Cl-2-F-phenyl 778 —CH₂—phen-1,3-diyl —O— 4-Cl-3-F-phenyl 779 —CH₂— phen-1,3-diyl —O—2,3-diMeO-phenyl 780 —CH₂— phen-1,3-diyl —O— 2,4-diMeO-phenyl 781 —CH₂—phen-1,3-diyl —O— 2,5-diMeO-phenyl 782 —CH₂— phen-1,3-diyl —O—2,6-diMeO-phenyl 783 —CH₂— phen-1,3-diyl —O— 3,4-diMeO-phenyl 784 —CH₂—phen-1,3-diyl —O— 3,5-diMeO-phenyl 785 —CH₂— phen-1,3-diyl —O—cyclopropyl 786 —CH₂— phen-1,3-diyl —O— cyclobutyl 787 —CH₂—phen-1,3-diyl —O— cyclopentyl 788 —CH₂— phen-1,3-diyl —O— cyclohexyl 789—CH₂— phen-1,3-diyl —O— 2-furanyl 790 —CH₂— phen-1,3-diyl —O— 2-thienyl791 —CH₂— phen-1,3-diyl CH₂CH₂ 2-imidazolyl 792 —CH₂— phen-1,3-diyl —O—2-pyridyl 793 —CH₂— phen-1,3-diyl —O— 3-pyridyl 794 —CH₂— phen-1,3-diyl—O— 4-pyridyl 795 —CH₂— phen-1,3-diyl CH₂CH₂ N-morpholinyl 796 —CH₂—phen-1,3-diyl CH₂CH₂ N-piperidinyl 797 —CH₂— phen-1,3-diyl —O—3-Me-2-pyridyl 798 —CH₂— phen-1,3-diyl —O— 4-Me-2-pyridyl 799 —CH₂—phen-1,3-diyl CH₂CH₂ 1-indolyl 800 —CH₂— phen-1,3-diyl —O—2-benzothienyl 801 —CH₂— phen-1,3-diyl —O— 2-benzofuranyl 802 —CH₂—phen-1,3-diyl CH₂CH₂ 1-benzimidazole 803 —CH₂— phen-1,3-diyl —O—2-naphthyl 804 —CH₂— pyridin-3, —O— phenyl 5-diyl 805 —CH₂— pyridin-3,—O— 3,3- 5-diyl diphenylmethyl 806 —CH₂— pyridin-3, —O— 2-F-phenyl5-diyl 807 —CH₂— pyridin-3, —O— 3-F-phenyl 5-diyl 808 —CH₂— pyridin-3,—O— 4-F-phenyl 5-diyl 809 —CH₂— pyridin-3, —O— 2-Cl-phenyl 5-diyl 810—CH₂— pyridin-3, —O— 3-Cl-phenyl 5-diyl 811 —CH₂— pyridin-3, —O—4-Cl-phenyl 5-diyl 812 —CH₂— pyridin-3, —O— 2-Me-phenyl 5-diyl 813 —CH₂—pyridin-3, —O— 3-Me-phenyl 5-diyl 814 —CH₂— pyridin-3, —O— 4-Me-phenyl5-diyl 815 —CH₂— pyridin-3, —O— 2-MeO-phenyl 5-diyl 816 —CH₂— pyridin-3,—O— 3-MeO-phenyl 5-diyl 817 —CH₂— pyridin-3, —O— 4-MeO-phenyl 5-diyl 818—CH₂— pyridin-3, —O— 2-MeS-phenyl 5-diyl 819 —CH₂— pyridin-3, —O—3-MeS-phenyl 5-diyl 820 —CH₂— pyridin-3, —O— 4-MeS-phenyl 5-diyl 821—CH₂— pyridin-3, —O— 2-F₃C-phenyl 5-diyl 822 —CH₂— pyridin-3, —O—3-F₃C-phenyl 5-diyl 823 —CH₂— pyridin-3, —O— 4-F₃C-phenyl 5-diyl 824—CH₂— pyridin-3, —O— 2,3-diF-phenyl 5-diyl 825 —CH₂— pyridin-3, —O—2,4-diF-phenyl 5-diyl 826 —CH₂— pyridin-3, —O— 2,5-diF-phenyl 5-diyl 827—CH₂— pyridin-3, —O— 2,6-diF-phenyl 5-diyl 828 —CH₂— pyridin-3, —O—3,4-diF-phenyl 5-diyl 829 —CH₂— pyridin-3, —O— 3,5-diF-phenyl 5-diyl 830—CH₂— pyridin-3, —O— 2,3-diCl-phenyl 5-diyl 831 —CH₂— pyridin-3, —O—2,4-diCl-phenyl 5-diyl 832 —CH₂— pyridin-3, —O— 2,5-diCl-phenyl 5-diyl833 —CH₂— pyridin-3, —O— 2,6-diCl-phenyl 5-diyl 834 —CH₂— pyridin-3, —O—3,4-diCl-phenyl 5-diyl 835 —CH₂— pyridin-3, —O— 3,5-diCl-phenyl 5-diyl836 —CH₂— pyridin-3, —O— 2-Cl-3-F-phenyl 5-diyl 837 —CH₂— pyridin-3, —O—2-Cl-4-F-phenyl 5-diyl 838 —CH₂— pyridin-3, —O— 2-Cl-5-F-phenyl 5-diyl839 —CH₂— pyridin-3, —O— 3-Cl-4-F-phenyl 5-diyl 840 —CH₂— pyridin-3, —O—3-Cl-5-F-phenyl 5-diyl 841 —CH₂— pyridin-3, —O— 4-Cl-2-F-phenyl 5-diyl842 —CH₂— pyridin-3, —O— 4-Cl-3-F-phenyl 5-diyl 843 —CH₂— pyridin-3, —O—2,3-diMeO-phenyl 5-diyl 844 —CH₂— pyridin-3, —O— 2,4-diMeO-phenyl 5-diyl845 —CH₂— pyridin-3, —O— 2,5-diMeO-phenyl 5-diyl 846 —CH₂— pyridin-3,—O— 2,6-diMeO-phenyl 5-diyl 847 —CH₂— pyridin-3, —O— 3,4-diMeO-phenyl5-diyl 848 —CH₂— pyridin-3, —O— 3,5-diMeO-phenyl 5-diyl 849 —CH₂—pyridin-3, —O— cyclopropyl 5-diyl 850 —CH₂— pyridin-3, —O— cyclobutyl5-diyl 851 —CH₂— pyridin-3, —O— cyclopentyl 5-diyl 852 —CH₂— pyridin-3,—O— cyclohexyl 5-diyl 853 —CH₂— pyridin-3, —O— 2-furanyl 5-diyl 854—CH₂— pyridin-3, —O— 2-thienyl 5-diyl 855 —CH₂— pyridin-3, CH₂CH₂2-imidazolyl 5-diyl 856 —CH₂— pyridin-3, —O— 2-pyridyl 5-diyl 857 —CH₂—pyridin-3, —O— 3-pyridyl 5-diyl 858 —CH₂— pyridin-3, —O— 4-pyridyl5-diyl 859 —CH₂— pyridin-3, CH₂CH₂ N-morpholinyl 5-diyl 860 —CH₂—pyridin-3, CH₂CH₂ N-piperidinyl 5-diyl 861 —CH₂— pyridin-3, —O—3-Me-2-pyridyl 5-diyl 862 —CH₂— pyridin-3, —O— 4-Me-2-pyridyl 5-diyl 863—CH₂— pyridin-3, CH₂CH₂ 1-indolyl 5-diyl 864 —CH₂— pyridin-3, —O—2-benzothienyl 5-diyl 865 —CH₂— pyridin-3, —O— 2-benzofuranyl 5-diyl 866—CH₂— pyridin-3, CH₂CH₂ 1-benzimidazole 5-diyl 867 —CH₂— pyridin-3, —O—2-naphthyl 5-diyl 868 —CH₂— pyridin-2, —O— phenyl 6-diyl 869 —CH₂—pyridin-2, —O— 3,3- 6-diyl diphenylmethyl 870 —CH₂— pyridin-2, —O—2-F-phenyl 6-diyl 871 —CH₂— pyridin-2, —O— 3-F-phenyl 6-diyl 872 —CH₂—pyridin-2, —O— 4-F-phenyl 6-diyl 873 —CH₂— pyridin-2, —O— 2-Cl-phenyl6-diyl 874 —CH₂— pyridin-2, —O— 3-Cl-phenyl 6-diyl 875 —CH₂— pyridin-2,—O— 4-Cl-phenyl 6-diyl 876 —CH₂— pyridin-2, —O— 2-Me-phenyl 6-diyl 877—CH₂— pyridin-2, —O— 3-Me-phenyl 6-diyl 878 —CH₂— pyridin-2, —O—4-Me-phenyl 6-diyl 879 —CH₂— pyridin-2, —O— 2-MeO-phenyl 6-diyl 880—CH₂— pyridin-2, —O— 3-MeO-phenyl 6-diyl 881 —CH₂— pyridin-2, —O—4-MeO-phenyl 6-diyl 882 —CH₂— pyridin-2, —O— 2-MeS-phenyl 6-diyl 883—CH₂— pyridin-2, —O— 3-MeS-phenyl 6-diyl 884 —CH₂— pyridin-2, —O—4-MeS-phenyl 6-diyl 885 —CH₂— pyridin-2, —O— 2-F₃C-phenyl 6-diyl 886—CH₂— pyridin-2, —O— 3-F₃C-phenyl 6-diyl 887 —CH₂— pyridin-2, —O—4-F₃C-phenyl 6-diyl 888 —CH₂— pyridin-2, —O— 2,3-diF-phenyl 6-diyl 889—CH₂— pyridin-2, —O— 2,4-diF-phenyl 6-diyl 890 —CH₂— pyridin-2, —O—2,5-diF-phenyl 6-diyl 891 —CH₂— pyridin-2, —O— 2,6-diF-phenyl 6-diyl 892—CH₂— pyridin-2, —O— 3,4-diF-phenyl 6-diyl 893 —CH₂— pyridin-2, —O—3,5-diF-phenyl 6-diyl 894 —CH₂— pyridin-2, —O— 2,3-diCl-phenyl 6-diyl895 —CH₂— pyridin-2, —O— 2,4-diCl-phenyl 6-diyl 896 —CH₂— pyridin-2, —O—2,5-diCl-phenyl 6-diyl 897 —CH₂— pyridin-2, —O— 2,6-diCl-phenyl 6-diyl898 —CH₂— pyridin-2, —O— 3,4-diCl-phenyl 6-diyl 899 —CH₂— pyridin-2, —O—3,5-diCl-phenyl 6-diyl 900 —CH₂— pyridin-2, —O— 2-Cl-3-F-phenyl 6-diyl901 —CH₂— pyridin-2, —O— 2-Cl-4-F-phenyl 6-diyl 902 —CH₂— pyridin-2, —O—2-Cl-5-F-phenyl 6-diyl 903 —CH₂— pyridin-2, —O— 3-Cl-4-F-phenyl 6-diyl904 —CH₂— pyridin-2, —O— 3-Cl-5-F-phenyl 6-diyl 905 —CH₂— pyridin-2, —O—4-Cl-2-F-phenyl 6-diyl 906 —CH₂— pyridin-2, —O— 4-Cl-3-F-phenyl 6-diyl907 —CH₂— pyridin-2, —O— 2,3-diMeO-phenyl 6-diyl 908 —CH₂— pyridin-2,—O— 2,4-diMeO-phenyl 6-diyl 909 —CH₂— pyridin-2, —O— 2,5-diMeO-phenyl6-diyl 910 —CH₂— pyridin-2, —O— 2,6-diMeO-phenyl 6-diyl 911 —CH₂—pyridin-2, —O— 3,4-diMeO-phenyl 6-diyl 912 —CH₂— pyridin-2, —O—3,5-diMeO-phenyl 6-diyl 913 —CH₂— pyridin-2, —O— cyclopropyl 6-diyl 914—CH₂— pyridin-2, —O— cyclobutyl 6-diyl 915 —CH₂— pyridin-2, —O—cyclopentyl 6-diyl 916 —CH₂— pyridin-2, —O— cyclohexyl 6-diyl 917 —CH₂—pyridin-2, —O— 2-furanyl 6-diyl 918 —CH₂— pyridin-2, —O— 2-thienyl6-diyl 919 —CH₂— pyridin-2, CH₂CH₂ 2-imidazolyl 6-diyl 920 —CH₂—pyridin-2, —O— 2-pyridyl 6-diyl 921 —CH₂— pyridin-2, —O— 3-pyridyl6-diyl 922 —CH₂— pyridin-2, —O— 4-pyridyl 6-diyl 923 —CH₂— pyridin-2,CH₂CH₂ N-morpholinyl 6-diyl 924 —CH₂— pyridin-2, CH₂CH₂ N-piperidinyl6-diyl 925 —CH₂— pyridin-2, —O— 3-Me-2-pyridyl 6-diyl 926 —CH₂—pyridin-2, —O— 4-Me-2-pyridyl 6-diyl 927 —CH₂— pyridin-2, CH₂CH₂1-indolyl 6-diyl 928 —CH₂— pyridin-2, —O— 2-benzothienyl 6-diyl 929—CH₂— pyridin-2, —O— 2-benzofuranyl 6-diyl 930 —CH₂— pyridin-2, CH₂CH₂1-benzimidazole 6-diyl 931 —CH₂— pyridin-2, —O— 2-naphthyl 6-diyl 932—CH₂— pyridin-2, —O— phenyl 4-diyl 933 —CH₂— pyridin-2, —O— 3,3- 4-diyldiphenylmethyl 934 —CH₂— pyridin-2, —O— 2-F-phenyl 4-diyl 935 —CH₂—pyridin-2, —O— 3-F-phenyl 4-diyl 936 —CH₂— pyridin-2, —O— 4-F-phenyl4-diyl 937 —CH₂— pyridin-2, —O— 2-Cl-phenyl 4-diyl 938 —CH₂— pyridin-2,—O— 3-Cl-phenyl 4-diyl 939 —CH₂— pyridin-2, —O— 4-Cl-phenyl 4-diyl 940—CH₂— pyridin-2, —O— 2-Me-phenyl 4-diyl 941 —CH₂— pyridin-2, —O—3-Me-phenyl 4-diyl 942 —CH₂— pyridin-2, —O— 4-Me-phenyl 4-diyl 943 —CH₂—pyridin-2, —O— 2-MeO-phenyl 4-diyl 944 —CH₂— pyridin-2, —O— 3-MeO-phenyl4-diyl 945 —CH₂— pyridin-2, —O— 4-MeO-phenyl 4-diyl 946 —CH₂— pyridin-2,—O— 2-MeS-phenyl 4-diyl 947 —CH₂— pyridin-2, —O— 3-MeS-phenyl 4-diyl 948—CH₂— pyridin-2, —O— 4-MeS-phenyl 4-diyl 949 —CH₂— pyridin-2, —O—2-F₃C-phenyl 4-diyl 950 —CH₂— pyridin-2, —O— 3-F₃C-phenyl 4-diyl 951—CH₂— pyridin-2, —O— 4-F₃C-phenyl 4-diyl 952 —CH₂— pyridin-2, —O—2,3-diF-phenyl 4-diyl 953 —CH₂— pyridin-2, —O— 2,4-diF-phenyl 4-diyl 954—CH₂— pyridin-2, —O— 2,5-diF-phenyl 4-diyl 955 —CH₂— pyridin-2, —O—2,6-diF-phenyl 4-diyl 956 —CH₂— pyridin-2, —O— 3,4-diF-phenyl 4-diyl 957—CH₂— pyridin-2, —O— 3,5-diF-phenyl 4-diyl 958 —CH₂— pyridin-2, —O—2,3-diCl-phenyl 4-diyl 959 —CH₂— pyridin-2, —O— 2,4-diCl-phenyl 4-diyl960 —CH₂— pyridin-2, —O— 2,5-diCl-phenyl 4-diyl 961 —CH₂— pyridin-2, —O—2,6-diCl-phenyl 4-diyl 962 —CH₂— pyridin-2, —O— 3,4-diCl-phenyl 4-diyl963 —CH₂— pyridin-2, —O— 3,5-diCl-phenyl 4-diyl 964 —CH₂— pyridin-2, —O—2-Cl-3-F-phenyl 4-diyl 965 —CH₂— pyridin-2, —O— 2-Cl-4-F-phenyl 4-diyl966 —CH₂— pyridin-2, —O— 2-Cl-5-F-phenyl 4-diyl 967 —CH₂— pyridin-2, —O—3-Cl-4-F-phenyl 4-diyl 968 —CH₂— pyridin-2, —O— 3-Cl-5-F-phenyl 4-diyl969 —CH₂— pyridin-2, —O— 4-Cl-2-F-phenyl 4-diyl 970 —CH₂— pyridin-2, —O—4-Cl-3-F-phenyl 4-diyl 971 —CH₂— pyridin-2, —O— 2,3-diMeO-phenyl 4-diyl972 —CH₂— pyridin-2, —O— 2,4-diMeO-phenyl 4-diyl 973 —CH₂— pyridin-2,—O— 2,5-diMeO-phenyl 4-diyl 974 —CH₂— pyridin-2, —O— 2,6-diMeO-phenyl4-diyl 975 —CH₂— pyridin-2, —O— 3,4-diMeO-phenyl 4-diyl 976 —CH₂—pyridin-2, —O— 3,5-diMeO-phenyl 4-diyl 977 —CH₂— pyridin-2, —O—cyclopropyl 4-diyl 978 —CH₂— pyridin-2, —O— cyclobutyl 4-diyl 979 —CH₂—pyridin-2, —O— cyclopentyl 4-diyl 980 —CH₂— pyridin-2, —O— cyclohexyl4-diyl 981 —CH₂— pyridin-2, —O— 2-furanyl 4-diyl 982 —CH₂— pyridin-2,—O— 2-thienyl 4-diyl 983 —CH₂— pyridin-2, CH₂CH₂ 2-imidazolyl 4-diyl 984—CH₂— pyridin-2, —O— 2-pyridyl 4-diyl 985 —CH₂— pyridin-2, —O— 3-pyridyl4-diyl 986 —CH₂— pyridin-2, —O— 4-pyridyl 4-diyl 987 —CH₂— pyridin-2,CH₂CH₂ N-morpholinyl 4-diyl 988 —CH₂— pyridin-2, CH₂CH₂ N-piperidinyl4-diyl 989 —CH₂— pyridin-2, —O— 3-Me-2-pyridyl 4-diyl 990 —CH₂—pyridin-2, —O— 4-Me-2-pyridyl 4-diyl 991 —CH₂— pyridin-2, CH₂CH₂1-indolyl 4-diyl 992 —CH₂— pyridin-2, —O— 2-benzothienyl 4-diyl 993—CH₂— pyridin-2, —O— 2-benzofuranyl 4-diyl 994 —CH₂— pyridin-2, CH₂CH₂1-benzimidazole 4-diyl 995 —CH₂— pyridin-2, —O— 2-naphthyl 4-diyl 996—CH₂— pyridin-4, —O— phenyl 2-diyl 997 —CH₂— pyridin-4, —O— 3,3- 2-diyldiphenylmethyl 998 —CH₂— pyridin-4, —O— 2-F-phenyl 2-diyl 999 —CH₂—pyridin-4, —O— 3-F-phenyl 2-diyl 1000 —CH₂— pyridin-4, —O— 4-F-phenyl2-diyl 1001 —CH₂— pyridin-4, —O— 2-Cl-phenyl 2-diyl 1002 —CH₂—pyridin-4, —O— 3-Cl-phenyl 2-diyl 1003 —CH₂— pyridin-4, —O— 4-Cl-phenyl2-diyl 1004 —CH₂— pyridin-4, —O— 2-Me-phenyl 2-diyl 1005 —CH₂—pyridin-4, —O— 3-Me-phenyl 2-diyl 1006 —CH₂— pyridin-4, —O— 4-Me-phenyl2-diyl 1007 —CH₂— pyridin-4, —O— 2-MeO-phenyl 2-diyl 1008 —CH₂—pyridin-4, —O— 3-MeO-phenyl 2-diyl 1009 —CH₂— pyridin-4, —O—4-MeO-phenyl 2-diyl 1010 —CH₂— pyridin-4, —O— 2-MeS-phenyl 2-diyl 1011—CH₂— pyridin-4, —O— 3-MeS-phenyl 2-diyl 1012 —CH₂— pyridin-4, —O—4-MeS-phenyl 2-diyl 1013 —CH₂— pyridin-4, —O— 2-F₃C-phenyl 2-diyl 1014—CH₂— pyridin-4, —O— 3-F₃C-phenyl 2-diyl 1015 —CH₂— pyridin-4, —O—4-F₃C-phenyl 2-diyl 1016 —CH₂— pyridin-4, —O— 2,3-diF-phenyl 2-diyl 1017—CH₂— pyridin-4, —O— 2,4-diF-phenyl 2-diyl 1018 —CH₂— pyridin-4, —O—2,5-diF-phenyl 2-diyl 1019 —CH₂— pyridin-4, —O— 2,6-diF-phenyl 2-diyl1020 —CH₂— pyridin-4, —O— 3,4-diF-phenyl 2-diyl 1021 —CH₂— pyridin-4,—O— 3,5-diF-phenyl 2-diyl 1022 —CH₂— pyridin-4, —O— 2,3-diCl-phenyl2-diyl 1023 —CH₂— pyridin-4, —O— 2,4-diCl-phenyl 2-diyl 1024 —CH₂—pyridin-4, —O— 2,5-diCl-phenyl 2-diyl 1025 —CH₂— pyridin-4, —O—2,6-diCl-phenyl 2-diyl 1026 —CH₂— pyridin-4, —O— 3,4-diCl-phenyl 2-diyl1027 —CH₂— pyridin-4, —O— 3,5-diCl-phenyl 2-diyl 1028 —CH₂— pyridin-4,—O— 2-Cl-3-F-phenyl 2-diyl 1029 —CH₂— pyridin-4, —O— 2-Cl-4-F-phenyl2-diyl 1030 —CH₂— pyridin-4, —O— 2-Cl-5-F-phenyl 2-diyl 1031 —CH₂—pyridin-4, —O— 3-Cl-4-F-phenyl 2-diyl 1032 —CH₂— pyridin-4, —O—3-Cl-5-F-phenyl 2-diyl 1033 —CH₂— pyridin-4, —O— 4-Cl-2-F-phenyl 2-diyl1034 —CH₂— pyridin-4, —O— 4-Cl-3-F-phenyl 2-diyl 1035 —CH₂— pyridin-4,—O— 2,3-diMeO-phenyl 2-diyl 1036 —CH₂— pyridin-4, —O— 2,4-diMeO-phenyl2-diyl 1037 —CH₂— pyridin-4, —O— 2,5-diMeO-phenyl 2-diyl 1038 —CH₂—pyridin-4, —O— 2,6-diMeO-phenyl 2-diyl 1039 —CH₂— pyridin-4, —O—3,4-diMeO-phenyl 2-diyl 1040 —CH₂— pyridin-4, —O— 3,5-diMeO-phenyl2-diyl 1041 —CH₂— pyridin-4, —O— cyclopropyl 2-diyl 1042 —CH₂—pyridin-4, —O— cyclobutyl 2-diyl 1043 —CH₂— pyridin-4, —O— cyclopentyl2-diyl 1044 —CH₂— pyridin-4, —O— cyclohexyl 2-diyl 1045 —CH₂— pyridin-4,—O— 2-furanyl 2-diyl 1046 —CH₂— pyridin-4, —O— 2-thienyl 2-diyl 1047—CH₂— pyridin-4, CH₂CH₂ 2-imidazolyl 2-diyl 1048 —CH₂— pyridin-4, —O—2-pyridyl 2-diyl 1049 —CH₂— pyridin-4, —O— 3-pyridyl 2-diyl 1050 —CH₂—pyridin-4, —O— 4-pyridyl 2-diyl 1051 —CH₂— pyridin-4, CH₂CH₂N-morpholinyl 2-diyl 1052 —CH₂— pyridin-4, CH₂CH₂ N-piperidinyl 2-diyl1053 —CH₂— pyridin-4, —O— 3-Me-2-pyridyl 2-diyl 1054 —CH₂— pyridin-4,—O— 4-Me-2-pyridyl 2-diyl 1055 —CH₂— pyridin-4, CH₂CH₂ 1-indolyl 2-diyl1056 —CH₂— pyridin-4, —O— 2-benzothienyl 2-diyl 1057 —CH₂— pyridin-4,—O— 2-benzofuranyl 2-diyl 1058 —CH₂— pyridin-4, CH₂CH₂ 1-benzimidazole2-diyl 1059 —CH₂— pyridin-4, —O— 2-naphthyl 2-diyl 1060 —CH₂—piperidin-1, —O— phenyl 3-diyl 1061 —CH₂— piperidin-1, —O— 3,3- 3-diyldiphenylinethyl 1062 —CH₂— piperidin-1, —O— 2-F-phenyl 3-diyl 1063 —CH₂—piperidin-1, —O— 3-F-phenyl 3-diyl 1064 —CH₂— piperidin-1, —O—4-F-phenyl 3-diyl 1065 —CH₂— piperidin-1, —O— 2-Cl-phenyl 3-diyl 1066—CH₂— piperidin-1, —O— 3-Cl-phenyl 3-diyl 1067 —CH₂— piperidin-1, —O—4-Cl-phenyl 3-diyl 1068 —CH₂— piperidin-1, —O— 2-Me-phenyl 3-diyl 1069—CH₂— piperidin-1, —O— 3-Me-phenyl 3-diyl 1070 —CH₂— piperidin-1, —O—4-Me-phenyl 3-diyl 1071 —CH₂— piperidin-1, —O— 2-MeO-phenyl 3-diyl 1072—CH₂— piperidin-1, —O— 3-MeO-phenyl 3-diyl 1073 —CH₂— piperidin-1, —O—4-MeO-phenyl 3-diyl 1074 —CH₂— piperidin-1, —O— 2-MeS-phenyl 3-diyl 1075—CH₂— piperidin-1, —O— 3-MeS-phenyl 3-diyl 1076 —CH₂— piperidin-1, —O—4-MeS-phenyl 3-diyl 1077 —CH₂— piperidin-1, —O— 2-F₃C-phenyl 3-diyl 1078—CH₂— piperidin-1, —O— 3-F₃C-phenyl 3-diyl 1079 —CH₂— piperidin-1, —O—4-F₃C-phenyl 3-diyl 1080 —CH₂— piperidin-1, —O— 2,3-diF-phenyl 3-diyl1081 —CH₂— piperidin-1, —O— 2,4-diF-phenyl 3-diyl 1082 —CH₂—piperidin-1, —O— 2,5-diF-phenyl 3-diyl 1083 —CH₂— piperidin-1, —O—2,6-diF-phenyl 3-diyl 1084 —CH₂— piperidin-1, —O— 3,4-diF-phenyl 3-diyl1085 —CH₂— piperidin-1, —O— 3,5-diF-phenyl 3-diyl 1086 —CH₂—piperidin-1, —O— 2,3-diCl-phenyl 3-diyl 1087 —CH₂— piperidin-1, —O—2,4-diCl-phenyl 3-diyl 1088 —CH₂— piperidin-1, —O— 2,5-diCl-phenyl3-diyl 1089 —CH₂— piperidin-1, —O— 2,6-diCl-phenyl 3-diyl 1090 —CH₂—piperidin-1, —O— 3,4-diCl-phenyl 3-diyl 1091 —CH₂— piperidin-1, —O—3,5-diCl-phenyl 3-diyl 1092 —CH₂— piperidin-1, —O— 2-Cl-3-F-phenyl3-diyl 1093 —CH₂— piperidin-1, —O— 2-Cl-4-F-phenyl 3-diyl 1094 —CH₂—piperidin-1, —O— 2-Cl-5-F-phenyl 3-diyl 1095 —CH₂— piperidin-1, —O—3-Cl-4-F-phenyl 3-diyl 1096 —CH₂— piperidin-1, —O— 3-Cl-5-F-phenyl3-diyl 1097 —CH₂— piperidin-1, —O— 4-Cl-2-F-phenyl 3-diyl 1098 —CH₂—piperidin-1, —O— 4-Cl-3-F-phenyl 3-diyl 1099 —CH₂— piperidin-1, —O—2,3-diMeO-phenyl 3-diyl 1100 —CH₂— piperidin-1, —O— 2,4-diMeO-phenyl3-diyl 1101 —CH₂— piperidin-1, —O— 2,5-diMeO-phenyl 3-diyl 1102 —CH₂—piperidin-1, —O— 2,6-diMeO-phenyl 3-diyl 1103 —CH₂— piperidin-1, —O—3,4-diMeO-phenyl 3-diyl 1104 —CH₂— piperidin-1, —O— 3,5-diMeO-phenyl3-diyl 1105 —CH₂— piperidin-1, —O— Cyclopropyl 3-diyl 1106 —CH₂—piperidin-1, —O— Cyclobutyl 3-diyl 1107 —CH₂— piperidin-1, —O—Cyclopentyl 3-diyl 1108 —CH₂— piperidin-1, —O— Cyclohexyl 3-diyl 1109—CH₂— piperidin-1, —O— 2-furanyl 3-diyl 1110 —CH₂— piperidin-1, —O—2-thienyl 3-diyl 1111 —CH₂— piperidin-1, CH₂CH₂ 2-imidazolyl 3-diyl 1112—CH₂— piperidin-1, —O— 2-pyridyl 3-diyl 1113 —CH₂— piperidin-1, —O—3-pyridyl 3-diyl 1114 —CH₂— piperidin-1, —O— 4-pyridyl 3-diyl 1115 —CH₂—piperidin-1, CH₂CH₂ N-morpholinyl 3-diyl 1116 —CH₂— piperidin-1, CH₂CH₂N-piperidinyl 3-diyl 1117 —CH₂— piperidin-1, —O— 3-Me-2-pyridyl 3-diyl1118 —CH₂— piperidin-1, —O— 4-Me-2-pyridyl 3-diyl 1119 —CH₂—piperidin-1, CH₂CH₂ 1-indolyl 3-diyl 1120 —CH₂— piperidin-1, —O—2-benzothienyl 3-diyl 1121 —CH₂— piperidin-1, —O— 2-benzofuranyl 3-diyl1122 —CH₂— piperidin-1, CH₂CH₂ 1-benzimidazole 3-diyl 1123 —CH₂—piperidin-1, —O— 2-naphthyl 3-diyl 1124 —CH₂— piperidin-3, —O— Phenyl1-diyl 1125 —CH₂— piperidin-3, —O— 3,3- 1-diyl diphenylmethyl 1126 —CH₂—piperidin-3, —O— 2-F-phenyl 1-diyl 1127 —CH₂— piperidin-3, —O—3-F-phenyl 1-diyl 1128 —CH₂— piperidin-3, —O— 4-F-phenyl 1-diyl 1129—CH₂— piperidin-3, —O— 2-Cl-phenyl 1-diyl 1130 —CH₂— piperidin-3, —O—3-Cl-phenyl 1-diyl 1131 —CH₂— piperidin-3, —O— 4-Cl-phenyl 1-diyl 1132—CH₂— piperidin-3, —O— 2-Me-phenyl 1-diyl 1133 —CH₂— piperidin-3, —O—3-Me-phenyl 1-diyl 1134 —CH₂— piperidin-3, —O— 4-Me-phenyl 1-diyl 1135—CH₂— piperidin-3, —O— 2-MeO-phenyl 1-diyl 1136 —CH₂— piperidin-3, —O—3-MeO-phenyl 1-diyl 1137 —CH₂— piperidin-3, —O— 4-MeO-phenyl 1-diyl 1138—CH₂— piperidin-3, —O— 2-MeS-phenyl 1-diyl 1139 —CH₂— piperidin-3, —O—3-MeS-phenyl 1-diyl 1140 —CH₂— piperidin-3, —O— 4-MeS-phenyl 1-diyl 1141—CH₂— piperidin-3, —O— 2-F₃C-phenyl 1-diyl 1142 —CH₂— piperidin-3, —O—3-F₃C-phenyl 1-diyl 1143 —CH₂— piperidin-3, —O— 4-F₃C-phenyl 1-diyl 1144—CH₂— piperidin-3, —O— 2,3-diF-phenyl 1-diyl 1145 —CH₂— piperidin-3, —O—2,4-diF-phenyl 1-diyl 1146 —CH₂— piperidin-3, —O— 2,5-diF-phenyl 1-diyl1147 —CH₂— piperidin-3, —O— 2,6-diF-phenyl 1-diyl 1148 —CH₂—piperidin-3, —O— 3,4-diF-phenyl 1-diyl 1149 —CH₂— piperidin-3, —O—3,5-diF-phenyl 1-diyl 1150 —CH₂— piperidin-3, —O— 2,3-diCl-phenyl 1-diyl1151 —CH₂— piperidin-3, —O— 2,4-diCl-phenyl 1-diyl 1152 —CH₂—piperidin-3, —O— 2,5-diCl-phenyl 1-diyl 1153 —CH₂— piperidin-3, —O—2,6-diCl-phenyl 1-diyl 1154 —CH₂— piperidin-3, —O— 3,4-diCl-phenyl1-diyl 1155 —CH₂— piperidin-3, —O— 3,5-diCl-phenyl 1-diyl 1156 —CH₂—piperidin-3, —O— 2-Cl-3-F-phenyl 1-diyl 1157 —CH₂— piperidin-3, —O—2-Cl-4-F-phenyl 1-diyl 1158 —CH₂— piperidin-3, —O— 2-Cl-5-F-phenyl1-diyl 1159 —CH₂— piperidin-3, —O— 3-Cl-4-F-phenyl 1-diyl 1160 —CH₂—piperidin-3, —O— 3-Cl-5-F-phenyl 1-diyl 1161 —CH₂— piperidin-3, —O—4-Cl-2-F-phenyl 1-diyl 1162 —CH₂— piperidin-3, —O— 4-Cl-3-F-phenyl1-diyl 1163 —CH₂— piperidin-3, —O— 2,3-diMeO-phenyl 1-diyl 1164 —CH₂—piperidin-3, —O— 2,4-diMeO-phenyl 1-diyl 1165 —CH₂— piperidin-3, —O—2,5-diMeO-phenyl 1-diyl 1166 —CH₂— piperidin-3, —O— 2,6-diMeO-phenyl1-diyl 1167 —CH₂— piperidin-3, —O— 3,4-diMeO-phenyl 1-diyl 1168 —CH₂—piperidin-3, —O— 3,5-diMeO-phenyl 1-diyl 1169 —CH₂— piperidin-3, —O—Cyclopropyl 1-diyl 1170 —CH₂— piperidin-3, —O— Cyclobutyl 1-diyl 1171—CH₂— piperidin-3, —O— Cyclopentyl 1-diyl 1172 —CH₂— piperidin-3, —O—Cyclohexyl 1-diyl 1173 —CH₂— piperidin-3, —O— 2-furanyl 1-diyl 1174—CH₂— piperidin-3, —O— 2-thienyl 1-diyl 1175 —CH₂— piperidin-3, CH₂CH₂2-imidazolyl 1-diyl 1176 —CH₂— piperidin-3, —O— 2-pyridyl 1-diyl 1177—CH₂— piperidin-3, —O— 3-pyridyl 1-diyl 1178 —CH₂— piperidin-3, —O—4-pyridyl 1-diyl 1179 —CH₂— piperidin-3, CH₂CH₂ N-morpholinyl 1-diyl1180 —CH₂— piperidin-3, CH₂CH₂ N-piperidinyl 1-diyl 1181 —CH₂—piperidin-3, —O— 3-Me-2-pyridyl 1-diyl 1182 —CH₂— piperidin-3, —O—4-Me-2-pyridyl 1-diyl 1183 —CH₂— piperidin-3, CH₂CH₂ 1-indolyl 1-diyl1184 —CH₂— piperidin-3, —O— 2-benzothienyl 1-diyl 1185 —CH₂—piperidin-3, —O— 2-benzofuranyl 1-diyl 1186 —CH₂— piperidin-3, CH₂CH₂1-benzimidazole 1-diyl 1187 —CH₂— piperidin-3, —O— 2-naphthyl 1-diyl1188 —CH₂— cyclohex- —O— Phenyl 1,3-diyl 1189 —CH₂— cyclohex- —O— 3,3-1,3-diyl diphenylmethyl 1190 —CH₂— cyclohex- —O— 2-F-phenyl 1,3-diyl1191 —CH₂— cyclohex- —O— 3-F-phenyl 1,3-diyl 1192 —CH₂— cyclohex- —O—4-F-phenyl 1,3-diyl 1193 —CH₂— cyclohex- —O— 2-Cl-phenyl 1,3-diyl 1194—CH₂— cyclohex- —O— 3-Cl-phenyl 1,3-diyl 1195 —CH₂— cyclohex- —O—4-Cl-phenyl 1,3-diyl 1196 —CH₂— cyclohex- —O— 2-Me-phenyl 1,3-diyl 1197—CH₂— cyclohex- —O— 3-Me-phenyl 1,3-diyl 1198 —CH₂— cyclohex- —O—4-Me-phenyl 1,3-diyl 1199 —CH₂— cyclohex- —O— 2-MeO-phenyl 1,3-diyl 1200—CH₂— cyclohex- —O— 3-MeO-phenyl 1,3-diyl 1201 —CH₂— cyclohex- —O—4-MeO-phenyl 1,3-diyl 1202 —CH₂— cyclohex- —O— 2-MeS-phenyl 1,3-diyl1203 —CH₂— cyclohex- —O— 3-MeS-phenyl 1,3-diyl 1204 —CH₂— cyclohex- —O—4-MeS-phenyl 1,3-diyl 1205 —CH₂— cyclohex- —O— 2-F₃C-phenyl 1,3-diyl1206 —CH₂— cyclohex- —O— 3-F₃C-phenyl 1,3-diyl 1207 —CH₂— cyclohex- —O—4-F₃C-phenyl 1,3-diyl 1208 —CH₂— cyclohex- —O— 2,3-diF-phenyl 1,3-diyl1209 —CH₂— cyclohex- —O— 2,4-diF-phenyl 1,3-diyl 1210 —CH₂— cyclohex-—O— 2,5-diF-phenyl 1,3-diyl 1211 —CH₂— cyclohex- —O— 2,6-diF-phenyl1,3-diyl 1212 —CH₂— cyclohex- —O— 3,4-diF-phenyl 1,3-diyl 1213 —CH₂—cyclohex- —O— 3,5-diF-phenyl 1,3-diyl 1214 —CH₂— cyclohex- —O—2,3-diCl-phenyl 1,3-diyl 1215 —CH₂— cyclohex- —O— 2,4-diCl-phenyl1,3-diyl 1216 —CH₂— cyclohex- —O— 2,5-diCl-phenyl 1,3-diyl 1217 —CH₂—cyclohex- —O— 2,6-diCl-phenyl 1,3-diyl 1218 —CH₂— cyclohex- —O—3,4-diCl-phenyl 1,3-diyl 1219 —CH₂— cyclohex- —O— 3,5-diCl-phenyl1,3-diyl 1220 —CH₂— cyclohex- —O— 2-Cl-3-F-phenyl 1,3-diyl 1221 —CH₂—cyclohex- —O— 2-Cl-4-F-phenyl 1,3-diyl 1222 —CH₂— cyclohex- —O—2-Cl-5-F-phenyl 1,3-diyl 1223 —CH₂— cyclohex- —O— 3-Cl-4-F-phenyl1,3-diyl 1224 —CH₂— cyclohex- —O— 3-Cl-5-F-phenyl 1,3-diyl 1225 —CH₂—cyclohex- —O— 4-Cl-2-F-phenyl 1,3-diyl 1226 —CH₂— cyclohex- —O—4-Cl-3-F-phenyl 1,3-diyl 1227 —CH₂— cyclohex- —O— 2,3-diMeO-phenyl1,3-diyl 1228 —CH₂— cyclohex- —O— 2,4-diMeO-phenyl 1,3-diyl 1229 —CH₂—cyclohex- —O— 2,5-diMeO-phenyl 1,3-diyl 1230 —CH₂— cyclohex- —O—2,6-diMeO-phenyl 1,3-diyl 1231 —CH₂— cyclohex- —O— 3,4-diMeO-phenyl1,3-diyl 1232 —CH₂— cyclohex- —O— 3,5-diMeO-phenyl 1,3-diyl 1233 —CH₂—cyclohex- —O— Cyclopropyl 1,3-diyl 1234 —CH₂— cyclohex- —O— Cyclobutyl1,3-diyl 1235 —CH₂— cyclohex- —O— Cyclopentyl 1,3-diyl 1236 —CH₂—cyclohex- —O— Cyclohexyl 1,3-diyl 1237 —CH₂— cyclohex- —O— 2-furanyl1,3-diyl 1238 —CH₂— cyclohex- —O— 2-thienyl 1,3-diyl 1239 —CH₂—cyclohex- CH₂CH₂ 2-imidazolyl 1,3-diyl 1240 —CH₂— cyclohex- —O—2-pyridyl 1,3-diyl 1241 —CH₂— cyclohex- —O— 3-pyridyl 1,3-diyl 1242—CH₂— cyclohex- —O— 4-pyridyl 1,3-diyl 1243 —CH₂— cyclohex- CH₂CH₂N-morpholinyl 1,3-diyl 1244 —CH₂— cyclohex- CH₂CH₂ N-piperidinyl1,3-diyl 1245 —CH₂— cyclohex- —O— 3-Me-2-pyridyl 1,3-diyl 1246 —CH₂—cyclohex- —O— 4-Me-2-pyridyl 1,3-diyl 1247 —CH₂— cyclohex- CH₂CH₂1-indolyl 1,3-diyl 1248 —CH₂— cyclohex- —O— 2-benzothienyl 1,3-diyl 1249—CH₂— cyclohex- —O— 2-benzofuranyl 1,3-diyl 1250 —CH₂— cyclohex- CH₂CH₂1-benzimidazole 1,3-diyl 1251 —CH₂— cyclohex- —O— 2-naphthyl 1,3-diyl1252 —CH₂— cyclopropan- —O— Phenyl 1,2-diyl 1253 —CH₂— cyclopropan- —O—3,3- 1,2-diyl diphenylmethyl 1254 —CH₂— cyclopropan- —O— 2-F-phenyl1,2-diyl 1255 —CH₂— cyclopropan- —O— 3-F-phenyl 1,2-diyl 1256 —CH₂—cyclopropan- —O— 4-F-phenyl 1,2-diyl 1257 —CH₂— cyclopropan- —O—2-Cl-phenyl 1,2-diyl 1258 —CH₂— cyclopropan- —O— 3-Cl-phenyl 1,2-diyl1259 —CH₂— cyclopropan- —O— 4-Cl-phenyl 1,2-diyl 1260 —CH₂— cyclopropan-—O— 2-Me-phenyl 1,2-diyl 1261 —CH₂— cyclopropan- —O— 3-Me-phenyl1,2-diyl 1262 —CH₂— cyclopropan- —O— 4-Me-phenyl 1,2-diyl 1263 —CH₂—cyclopropan- —O— 2-MeO-phenyl 1,2-diyl 1264 —CH₂— cyclopropan- —O—3-MeO-phenyl 1,2-diyl 1265 —CH₂— cyclopropan- —O— 4-MeO-phenyl 1,2-diyl1266 —CH₂— cyclopropan- —O— 2-MeS-phenyl 1,2-diyl 1267 —CH₂—cyclopropan- —O— 3-MeS-phenyl 1,2-diyl 1268 —CH₂— cyclopropan- —O—4-MeS-phenyl 1,2-diyl 1269 —CH₂— cyclopropan- —O— 2-F₃C-phenyl 1,2-diyl1270 —CH₂— cyclopropan- —O— 3-F₃C-phenyl 1,2-diyl 1271 —CH₂—cyclopropan- —O— 4-F₃C-phenyl 1,2-diyl 1272 —CH₂— cyclopropan- —O—2,3-diF-phenyl 1,2-diyl 1273 —CH₂— cyclopropan- —O— 2,4-diF-phenyl1,2-diyl 1274 —CH₂— cyclopropan- —O— 2,5-diF-phenyl 1,2-diyl 1275 —CH₂—cyclopropan- —O— 2,6-diF-phenyl 1,2-diyl 1276 —CH₂— cyclopropan- —O—3,4-diF-phenyl 1,2-diyl 1277 —CH₂— cyclopropan- —O— 3,5-diF-phenyl1,2-diyl 1278 —CH₂— cyclopropan- —O— 2,3-diCl-phenyl 1,2-diyl 1279 —CH₂—cyclopropan- —O— 2,4-diCl-phenyl 1,2-diyl 1280 —CH₂— cyclopropan- —O—2,5-diCl-phenyl 1,2-diyl 1281 —CH₂— cyclopropan- —O— 2,6-diCl-phenyl1,2-diyl 1282 —CH₂— cyclopropan- —O— 3,4-diCl-phenyl 1,2-diyl 1283 —CH₂—cyclopropan- —O— 3,5-diCl-phenyl 1,2-diyl 1284 —CH₂— cyclopropan- —O—2-Cl-3-F-phenyl 1,2-diyl 1285 —CH₂— cyclopropan- —O— 2-Cl-4-F-phenyl1,2-diyl 1286 —CH₂— cyclopropan- —O— 2-Cl-5-F-phenyl 1,2-diyl 1287 —CH₂—cyclopropan- —O— 3-Cl-4-F-phenyl 1,2-diyl 1288 —CH₂— cyclopropan- —O—3-Cl-5-F-phenyl 1,2-diyl 1289 —CH₂— cyclopropan- —O— 4-Cl-2-F-phenyl1,2-diyl 1290 —CH₂— cyclopropan- —O— 4-Cl-3-F-phenyl 1,2-diyl 1291 —CH₂—cyclopropan- —O— 2,3-diMeO-phenyl 1,2-diyl 1292 —CH₂— cyclopropan- —O—2,4-diMeO-phenyl 1,2-diyl 1293 —CH₂— cyclopropan- —O— 2,5-diMeO-phenyl1,2-diyl 1294 —CH₂— cyclopropan- —O— 2,6-diMeO-phenyl 1,2-diyl 1295—CH₂— cyclopropan- —O— 3,4-diMeO-phenyl 1,2-diyl 1296 —CH₂— cyclopropan-—O— 3,5-diMeO-phenyl 1,2-diyl 1297 —CH₂— cyclopropan- —O— Cyclopropyl1,2-diyl 1298 —CH₂— cyclopropan- —O— Cyclobutyl 1,2-diyl 1299 —CH₂—cyclopropan- —O— Cyclopentyl 1,2-diyl 1300 —CH₂— cyclopropan- —O—Cyclohexyl 1,2-diyl 1301 —CH₂— cyclopropan- —O— 2-furanyl 1,2-diyl 1302—CH₂— cyclopropan- —O— 2-thienyl 1,2-diyl 1303 —CH₂— cyclopropan- CH₂CH₂2-imidazolyl 1,2-diyl 1304 —CH₂— cyclopropan- —O— 2-pyridyl 1,2-diyl1305 —CH₂— cyclopropan- —O— 3-pyridyl 1,2-diyl 1306 —CH₂— cyclopropan-—O— 4-pyridyl 1,2-diyl 1307 —CH₂— cyclopropan- CH₂CH₂ N-morpholinyl1,2-diyl 1308 —CH₂— cyclopropan- CH₂CH₂ N-piperidinyl 1,2-diyl 1309—CH₂— cyclopropan- —O— 3-Me-2-pyridyl 1,2-diyl 1310 —CH₂— cyclopropan-—O— 4-Me-2-pyridyl 1,2-diyl 1311 —CH₂— cyclopropan- CH₂CH₂ 1-indolyl1,2-diyl 1312 —CH₂— cyclopropan- —O— 2-benzothienyl 1,2-diyl 1313 —CH₂—cyclopropan- —O— 2-benzofuranyl 1,2-diyl 1314 —CH₂— cyclopropan- CH₂CH₂1-benzimidazole 1,2-diyl 1315 —CH₂— cyclopropan- —O— 2-naphthyl 1,2-diyl1316 —CH₂— cyclopentan- —O— Phenyl 1,3-diyl 1317 —CH₂— cyclopentan- —O—3,3- 1,3-diyl diphenylmethyl 1318 —CH₂— cyclopentan- —O— 2-F-phenyl1,3-diyl 1319 —CH₂— cyclopentan- —O— 3-F-phenyl 1,3-diyl 1320 —CH₂—cyclopentan- —O— 4-F-phenyl 1,3-diyl 1321 —CH₂— cyclopentan- —O—2-Cl-phenyl 1,3-diyl 1322 —CH₂— cyclopentan- —O— 3-Cl-phenyl 1,3-diyl1323 —CH₂— cyclopentan- —O— 4-Cl-phenyl 1,3-diyl 1324 —CH₂— cyclopentan-—O— 2-Me-phenyl 1,3-diyl 1325 —CH₂— cyclopentan- —O— 3-Me-phenyl1,3-diyl 1326 —CH₂— cyclopentan- —O— 4-Me-phenyl 1,3-diyl 1327 —CH₂—cyclopentan- —O— 2-MeO-phenyl 1,3-diyl 1328 —CH₂— cyclopentan- —O—3-MeO-phenyl 1,3-diyl 1329 —CH₂— cyclopentan- —O— 4-MeO-phenyl 1,3-diyl1330 —CH₂— cyclopentan- —O— 2-MeS-phenyl 1,3-diyl 1331 —CH₂—cyclopentan- —O— 3-MeS-phenyl 1,3-diyl 1332 —CH₂— cyclopentan- —O—4-MeS-phenyl 1,3-diyl 1333 —CH₂— cyclopentan- —O— 2-F₃C-phenyl 1,3-diyl1334 —CH₂— cyclopentan- —O— 3-F₃C-phenyl 1,3-diyl 1335 —CH₂—cyclopentan- —O— 4-F₃C-phenyl 1,3-diyl 1336 —CH₂— cyclopentan- —O—2,3-diF-phenyl 1,3-diyl 1337 —CH₂— cyclopentan- —O— 2,4-diF-phenyl1,3-diyl 1338 —CH₂— cyclopentan- —O— 2,5-diF-phenyl 1,3-diyl 1339 —CH₂—cyclopentan- —O— 2,6-diF-phenyl 1,3-diyl 1340 —CH₂— cyclopentan- —O—3,4-diF-phenyl 1,3-diyl 1341 —CH₂— cyclopentan- —O— 3,5-diF-phenyl1,3-diyl 1342 —CH₂— cyclopentan- —O— 2,3-diCl-phenyl 1,3-diyl 1343 —CH₂—cyclopentan- —O— 2,4-diCl-phenyl 1,3-diyl 1344 —CH₂— cyclopentan- —O—2,5-diCl-phenyl 1,3-diyl 1345 —CH₂— cyclopentan- —O— 2,6-diCl-phenyl1,3-diyl 1346 —CH₂— cyclopentan- —O— 3,4-diCl-phenyl 1,3-diyl 1347 —CH₂—cyclopentan- —O— 3,5-diCl-phenyl 1,3-diyl 1348 —CH₂— cyclopentan- —O—2-Cl-3-F-phenyl 1,3-diyl 1349 —CH₂— cyclopentan- —O— 2-Cl-4-F-phenyl1,3-diyl 1350 —CH₂— cyclopentan- —O— 2-Cl-5-F-phenyl 1,3-diyl 1351 —CH₂—cyclopentan- —O— 3-Cl-4-F-phenyl 1,3-diyl 1352 —CH₂— cyclopentan- —O—3-Cl-5-F-phenyl 1,3-diyl 1353 —CH₂— cyclopentan- —O— 4-Cl-2-F-phenyl1,3-diyl 1354 —CH₂— cyclopentan- —O— 4-Cl-3-F-phenyl 1,3-diyl 1355 —CH₂—cyclopentan- —O— 2,3-diMeO-phenyl 1,3-diyl 1356 —CH₂— cyclopentan- —O—2,4-diMeO-phenyl 1,3-diyl 1357 —CH₂— cyclopentan- —O— 2,5-diMeO-phenyl1,3-diyl 1358 —CH₂— cyclopentan- —O— 2,6-diMeO-phenyl 1,3-diyl 1359—CH₂— cyclopentan- —O— 3,4-diMeO-phenyl 1,3-diyl 1360 —CH₂— cyclopentan-—O— 3,5-diMeO-phenyl 1,3-diyl 1361 —CH₂— cyclopentan- —O— Cyclopropyl1,3-diyl 1362 —CH₂— cyclopentan- —O— Cyclobutyl 1,3-diyl 1363 —CH₂—cyclopentan- —O— Cyclopentyl 1,3-diyl 1364 —CH₂— cyclopentan- —O—Cyclohexyl 1,3-diyl 1365 —CH₂— cyclopentan- —O— 2-furanyl 1,3-diyl 1366—CH₂— cyclopentan- —O— 2-thienyl 1,3-diyl 1367 —CH₂— cyclopentan- CH₂CH₂2-imidazolyl 1,3-diyl 1368 —CH₂— cyclopentan- —O— 2-pyridyl 1,3-diyl1369 —CH₂— cyclopentan- —O— 3-pyridyl 1,3-diyl 1370 —CH₂— cyclopentan-—O— 4-pyridyl 1,3-diyl 1371 —CH₂— cyclopentan- CH₂CH₂ N-morpholinyl1,3-diyl 1372 —CH₂— cyclopentan- CH₂CH₂ N-piperidinyl 1,3-diyl 1373—CH₂— cyclopentan- —O— 3-Me-2-pyridyl 1,3-diyl 1374 —CH₂— cyclopentan-—O— 4-Me-2-pyridyl 1,3-diyl 1375 —CH₂— cyclopentan- CH₂CH₂ 1-indolyl1,3-diyl 1376 —CH₂— cyclopentan- —O— 2-benzothienyl 1,3-diyl 1377 —CH₂—cyclopentan- —O— 2-benzofuranyl 1,3-diyl 1378 —CH₂— cyclopentan- CH₂CH₂1-benzimidazole 1,3-diyl 1379 —CH₂— cyclopentan- —O— 2-naphthyl 1,3-diyl1380 —CH₂— bond bond phenyl 1381 —CH₂— bond bond 3,3-diphenyl 1382 —CH₂—bond bond 2-F-phenyl 1383 —CH₂— bond bond 3-F-phenyl 1384 —CH₂— bondbond 4-F-phenyl 1385 —CH₂— bond bond 2-Cl-phenyl 1386 —CH₂— bond bond3-Cl-phenyl 1387 —CH₂— bond bond 4-Cl-phenyl 1388 —CH₂— bond bond2-Me-phenyl 1389 —CH₂— bond bond 3-Me-phenyl 1390 —CH₂— bond bond4-Me-phenyl 1391 —CH₂— bond bond 2-MeO-phenyl 1392 —CH₂— bond bond3-MeO-phenyl 1393 —CH₂— bond bond 4-MeO-phenyl 1394 —CH₂— bond bond2-MeS-phenyl 1395 —CH₂— bond bond 3-MeS-phenyl 1396 —CH₂— bond bond4-MeS-phenyl 1397 —CH₂— bond bond 2-F₃C-phenyl 1398 —CH₂— bond bond3-F₃C-phenyl 1399 —CH₂— bond bond 4-F₃C-phenyl 1400 —CH₂— bond bond2,3-diF-phenyl 1401 —CH₂— bond bond 2,4-diF-phenyl 1402 —CH₂— bond bond2,5-diF-phenyl 1403 —CH₂— bond bond 2,6-diF-phenyl 1404 —CH₂— bond bond3,4-diF-phenyl 1405 —CH₂— bond bond 3,5-diF-phenyl 1406 —CH₂— bond bond2,3-diCl-phenyl 1407 —CH₂— bond bond 2,4-diCl-phenyl 1408 —CH₂— bondbond 2,5-diCl-phenyl 1409 —CH₂— bond bond 2,6-diCl-phenyl 1410 —CH₂—bond bond 3,4-diCl-phenyl 1411 —CH₂— bond bond 3,5-diCl-phenyl 1412—CH₂— bond bond 2-Cl-3-F-phenyl 1413 —CH₂— bond bond 2-Cl-4-F-phenyl1414 —CH₂— bond bond 2-Cl-5-F-phenyl 1415 —CH₂— bond bond3-Cl-4-F-phenyl 1416 —CH₂— bond bond 3-Cl-5-F-phenyl 1417 —CH₂— bondbond 4-Cl-2-F-phenyl 1418 —CH₂— bond bond 4-Cl-3-F-phenyl 1419 —CH₂—bond bond 2,3-diMeO-phenyl 1420 —CH₂— bond bond 2,4-diMeO-phenyl 1421—CH₂— bond bond 2,5-diMeO-phenyl 1422 —CH₂— bond bond 2,6-diMeO-phenyl1423 —CH₂— bond bond 3,4-diMeO-phenyl 1424 —CH₂— bond bond3,5-diMeO-phenyl 1425 —CH₂— bond bond cyclopropyl 1426 —CH₂— bond bondcyclobutyl 1427 —CH₂— bond bond cyclopentyl 1428 —CH₂— bond bondcyclohexyl 1429 —CH₂— bond bond 2-furanyl 1430 —CH₂— bond bond 2-thienyl1431 —CH₂— bond bond 2-imidazolyl 1432 —CH₂— bond bond 2-pyridyl 1433—CH₂— bond bond 3-pyridyl 1434 —CH₂— bond bond 4-pyridyl 1435 —CH₂— bondbond N-morpholinyl 1436 —CH₂— bond bond N-piperidinyl 1437 —CH₂— bondbond 3-Me-2-pyridyl 1438 —CH₂— bond bond 4-Me-2-pyridyl 1439 —CH₂— bondbond 1-indolyl 1440 —CH₂— bond bond 2-benzothienyl 1441 —CH₂— bond bond2-benzofuranyl 1442 —CH₂— bond bond 1-benzimidazole 1443 —CH₂— bond bond2-naphthyl 1444 —CH₂CH₂— bond bond phenyl 1445 —CH₂CH₂— bond bond3,3-diphenyl 1446 —CH₂CH₂— bond bond 2-F-phenyl 1447 —CH₂CH₂— bond bond3-F-phenyl 1448 —CH₂CH₂— bond bond 4-F-phenyl 1449 —CH₂CH₂— bond bond2-Cl-phenyl 1450 —CH₂CH₂— bond bond 3-Cl-phenyl 1451 —CH₂CH₂— bond bond4-Cl-phenyl 1452 —CH₂CH₂— bond bond 2-Me-phenyl 1453 —CH₂CH₂— bond bond3-Me-phenyl 1454 —CH₂CH₂— bond bond 4-Me-phenyl 1455 —CH₂CH₂— bond bond2-MeO-phenyl 1456 —CH₂CH₂— bond bond 3-MeO-phenyl 1457 —CH₂CH₂— bondbond 4-MeO-phenyl 1458 —CH₂CH₂— bond bond 2-MeS-phenyl 1459 —CH₂CH₂—bond bond 3-MeS-phenyl 1460 —CH₂CH₂— bond bond 4-MeS-phenyl 1461—CH₂CH₂— bond bond 2-F₃C-phenyl 1462 —CH₂CH₂— bond bond 3-F₃C-phenyl1463 —CH₂CH₂— bond bond 4-F₃C-phenyl 1464 —CH₂CH₂— bond bond2,3-diF-phenyl 1465 —CH₂CH₂— bond bond 2,4-diF-phenyl 1466 —CH₂CH₂— bondbond 2,5-diF-phenyl 1467 —CH₂CH₂— bond bond 2,6-diF-phenyl 1468 —CH₂CH₂—bond bond 3,4-diF-phenyl 1469 —CH₂CH₂— bond bond 3,5-diF-phenyl 1470—CH₂CH₂— bond bond 2,3-diCl-phenyl 1471 —CH₂CH₂— bond bond2,4-diCl-phenyl 1472 —CH₂CH₂— bond bond 2,5-diCl-phenyl 1473 —CH₂CH₂—bond bond 2,6-diCl-phenyl 1474 —CH₂CH₂— bond bond 3,4-diCl-phenyl 1475—CH₂CH₂— bond bond 3,5-diCl-phenyl 1476 —CH₂CH₂— bond bond2-Cl-3-F-phenyl 1477 —CH₂CH₂— bond bond 2-Cl-4-F-phenyl 1478 —CH₂CH₂—bond bond 2-Cl-5-F-phenyl 1479 —CH₂CH₂— bond bond 3-Cl-4-F-phenyl 1480—CH₂CH₂— bond bond 3-Cl-5-F-phenyl 1481 —CH₂CH₂— bond bond4-Cl-2-F-phenyl 1482 —CH₂CH₂— bond bond 4-Cl-3-F-phenyl 1483 —CH₂CH₂—bond bond 2,3-diMeO-phenyl 1484 —CH₂CH₂— bond bond 2,4-diMeO-phenyl 1485—CH₂CH₂— bond bond 2,5-diMeO-phenyl 1486 —CH₂CH₂— bond bond2,6-diMeO-phenyl 1487 —CH₂CH₂— bond bond 3,4-diMeO-phenyl 1488 —CH₂CH₂—bond bond 3,5-diMeO-phenyl 1489 —CH₂CH₂— bond bond cyclopropyl 1490—CH₂CH₂— bond bond cyclobutyl 1491 —CH₂CH₂— bond bond cyclopentyl 1492—CH₂CH₂— bond bond cyclohexyl 1493 —CH₂CH₂— bond bond 2-furanyl 1494—CH₂CH₂— bond bond 2-thienyl 1495 —CH₂CH₂— bond bond 2-imidazolyl 1496—CH₂CH₂— bond bond 2-pyridyl 1497 —CH₂CH₂— bond bond 3-pyridyl 1498—CH₂CH₂— bond bond 4-pyridyl 1499 —CH₂CH₂— bond bond N-morpholinyl 1500—CH₂CH₂— bond bond N-piperidinyl 1501 —CH₂CH₂— bond bond 3-Me-2-pyridyl1502 —CH₂CH₂— bond bond 4-Me-2-pyridyl 1503 —CH₂CH₂— bond bond 1-indolyl1504 —CH₂CH₂— bond bond 2-benzothienyl 1505 —CH₂CH₂— bond bond2-benzofuranyl 1506 —CH₂CH₂— bond bond 1-benzimidazole 1507 —CH₂CH₂—bond bond 2-naphthyl 1508 —CH₂CH₂ bond bond phenyl CH₂— 1509 —CH₂CH₂bond bond 3,3-diphenyl CH₂— 1510 —CH₂CH₂ bond bond 2-F-phenyl CH₂— 1511—CH₂CH₂ bond bond 3-F-phenyl CH₂— 1512 —CH₂CH₂ bond bond 4-F-phenyl CH₂—1513 —CH₂CH₂ bond bond 2-Cl-phenyl CH₂— 1514 —CH₂CH₂ bond bond3-Cl-phenyl CH₂— 1515 —CH₂CH₂ bond bond 4-Cl-phenyl CH₂— 1516 —CH₂CH₂bond bond 2-Me-phenyl CH₂— 1517 —CH₂CH₂ bond bond 3-Me-phenyl CH₂— 1518—CH₂CH₂ bond bond 4-Me-phenyl CH₂— 1519 —CH₂CH₂ bond bond 2-MeO-phenylCH₂— 1520 —CH₂CH₂ bond bond 3-MeO-phenyl CH₂— 1521 —CH₂CH₂ bond bond4-MeO-phenyl CH₂— 1522 —CH₂CH₂ bond bond 2-MeS-phenyl CH₂— 1523 —CH₂CH₂bond bond 3-MeS-phenyl CH₂— 1524 —CH₂CH₂ bond bond 4-MeS-phenyl CH₂—1525 —CH₂CH₂ bond bond 2-F₃C-phenyl CH₂— 1526 —CH₂CH₂ bond bond3-F₃C-phenyl CH₂— 1527 —CH₂CH₂ bond bond 4-F₃C-phenyl CH₂— 1528 —CH₂CH₂bond bond 2,3-diF-phenyl CH₂— 1529 —CH₂CH₂ bond bond 2,4-diF-phenyl CH₂—1530 —CH₂CH₂ bond bond 2,5-diF-phenyl CH₂— 1531 —CH₂CH₂ bond bond2,6-diF-phenyl CH₂— 1532 —CH₂CH₂ bond bond 3,4-diF-phenyl CH₂— 1533—CH₂CH₂ bond bond 3,5-diF-phenyl CH₂— 1534 —CH₂CH₂ bond bond2,3-diCl-phenyl CH₂— 1535 —CH₂CH₂ bond bond 2,4-diCl-phenyl CH₂— 1536—CH₂CH₂ bond bond 2,5-diCl-phenyl CH₂— 1537 —CH₂CH₂ bond bond2,6-diCl-phenyl CH₂— 1538 —CH₂CH₂ bond bond 3,4-diCl-phenyl CH₂— 1539—CH₂CH₂ bond bond 3,5-diCl-phenyl CH₂— 1540 —CH₂CH₂ bond bond2-Cl-3-F-phenyl CH₂— 1541 —CH₂CH₂ bond bond 2-Cl-4-F-phenyl CH₂— 1542—CH₂CH₂ bond bond 2-Cl-5-F-phenyl CH₂— 1543 —CH₂CH₂ bond bond3-Cl-4-F-phenyl CH₂— 1544 —CH₂CH₂ bond bond 3-Cl-5-F-phenyl CH₂— 1545—CH₂CH₂ bond bond 4-Cl-2-F-phenyl CH₂— 1546 —CH₂CH₂ bond bond4-Cl-3-F-phenyl CH₂— 1547 —CH₂CH₂ bond bond 2,3-diMeO-phenyl CH₂— 1548—CH₂CH₂ bond bond 2,4-diMeO-phenyl CH₂— 1549 —CH₂CH₂ bond bond2,5-diMeO-phenyl CH₂— 1550 —CH₂CH₂ bond bond 2,6-diMeO-phenyl CH₂— 1551—CH₂CH₂ bond bond 3,4-diMeO-phenyl CH₂— 1552 —CH₂CH₂ bond bond3,5-diMeO-phenyl CH₂— 1553 —CH₂CH₂ bond bond cyclopropyl CH₂— 1554—CH₂CH₂ bond bond cyclobutyl CH₂— 1555 —CH₂CH₂ bond bond cyclopentylCH₂— 1556 —CH₂CH₂ bond bond cyclohexyl CH₂— 1557 —CH₂CH₂ bond bond2-furanyl CH₂— 1558 —CH₂CH₂ bond bond 2-thienyl CH₂— 1559 —CH₂CH₂ bondbond 2-imidazolyl CH₂— 1560 —CH₂CH₂ bond bond 2-pyridyl CH₂— 1561—CH₂CH₂ bond bond 3-pyridyl CH₂— 1562 —CH₂CH₂ bond bond 4-pyridyl CH₂—1563 —CH₂CH₂ bond bond N-morpholinyl CH₂— 1564 —CH₂CH₂ bond bondN-piperidinyl CH₂— 1565 —CH₂CH₂ bond bond 3-Me-2-pyridyl CH₂— 1566—CH₂CH₂ bond bond 4-Me-2-pyridyl CH₂— 1567 —CH₂CH₂ bond bond 1-indolylCH₂— 1568 —CH₂CH₂ bond bond 2-benzothienyl CH₂— 1569 —CH₂CH₂ bond bond2-benzofuranyl CH₂— 1570 —CH₂CH₂ bond bond 1-benzimidazole CH₂— 1571—CH₂CH₂ bond bond 2-naphthyl CH₂— 1572 —CH₂CH₂— bond —O— phenyl 1573—CH₂CH₂— bond —O— 3,3- diphenylmethyl 1574 —CH₂CH₂— bond —O— 2-F-phenyl1575 —CH₂CH₂— bond —O— 3-F-phenyl 1576 —CH₂CH₂— bond —O— 4-F-phenyl 1577—CH₂CH₂— bond —O— 2-Cl-phenyl 1578 —CH₂CH₂— bond —O— 3-Cl-phenyl 1579—CH₂CH₂— bond —O— 4-Cl-phenyl 1580 —CH₂CH₂— bond —O— 2-Me-phenyl 1581—CH₂CH₂— bond —O— 3-Me-phenyl 1582 —CH₂CH₂— bond —O— 4-Me-phenyl 1583—CH₂CH₂— bond —O— 2-MeO-phenyl 1584 —CH₂CH2— bond —O— 3-MeO-phenyl 1585—CH₂CH2— bond —O— 4-MeO-phenyl 1586 —CH₂CH₂— bond —O— 2-MeS-phenyl 1587—CH₂CH₂— bond —O— 3-MeS-phenyl 1588 —CH₂CH₂— bond —O— 4-MeS-phenyl 1589—CH₂CH₂— bond —O— 2-F₃C-phenyl 1590 —CH₂CH₂— bond —O— 3-F₃C-phenyl 1591—CH₂CH₂— bond —O— 4-F₃C-phenyl 1592 —CH₂CH₂— bond —O— 2,3-diF-phenyl1593 —CH₂CH₂— bond —O— 2,4-diF-phenyl 1594 —CH₂CH₂— bond —O—2,5-diF-phenyl 1595 —CH₂CH₂— bond —O— 2,6-diF-phenyl 1596 —CH₂CH₂— bond—O— 3,4-diF-phenyl 1597 —CH₂CH₂— bond —O— 3,5-diF-phenyl 1598 —CH₂CH₂—bond —O— 2,3-diCl-phenyl 1599 —CH₂CH₂— bond —O— 2,4-diCl-phenyl 1600—CH₂CH₂— bond —O— 2,5-diCl-phenyl 1601 —CH₂CH₂— bond —O— 2,6-diCl-phenyl1602 —CH₂CH₂— bond —O— 3,4-diCl-phenyl 1603 —CH₂CH₂— bond —O—3,5-diCl-phenyl 1604 —CH₂CH₂— bond —O— 2-Cl-3-F-phenyl 1605 —CH₂CH₂—bond —O— 2-Cl-4-F-phenyl 1606 —CH₂CH₂— bond —O— 2-Cl-5-F-phenyl 1607—CH₂CH₂— bond —O— 3-Cl-4-F-phenyl 1608 —CH₂CH₂— bond —O— 3-Cl-5-F-phenyl1609 —CH₂CH₂— bond —O— 4-Cl-2-F-phenyl 1610 —CH₂CH₂— bond —O—4-Cl-3-F-phenyl 1611 —CH₂CH₂— bond —O— 2,3-diMeO-phenyl 1612 —CH₂CH₂—bond —O— 2,4-diMeO-phenyl 1613 —CH₂CH₂— bond —O— 2,5-diMeO-phenyl 1614—CH₂CH₂— bond —O— 2,6-diMeO-phenyl 1615 —CH₂CH₂— bond —O—3,4-diMeO-phenyl 1616 —CH₂CH₂— bond —O— 3,5-diMeO-phenyl 1617 —CH₂CH₂—bond —O— cyclopropyl 1618 —CH₂CH₂— bond —O— cyclobutyl 1619 —CH₂CH₂—bond —O— cyclopentyl 1620 —CH₂CH₂— bond —O— cyclohexyl 1621 —CH₂CH₂—bond —O— 2-furanyl 1622 —CH₂CH₂— bond —O— 2-thienyl 1623 —CH₂CH₂— bond—O— 2-pyridyl 1624 —CH₂CH₂— bond —O— 3-pyridyl 1625 —CH₂CH₂— bond —O—4-pyridyl 1626 —CH₂CH₂— bond —O— 3-Me-2-pyridyl 1627 —CH₂CH₂— bond —O—4-Me-2-pyridyl 1628 —CH₂CH₂— bond —O— 2-benzothienyl 1629 —CH₂CH₂— bond—O— 2-benzofuranyl 1630 —CH₂CH₂— bond —O— 2-naphthyl 1631 —CH₂CH₂ bond—O— phenyl CH₂— 1632 —CH₂CH₂ bond —O— 3,3- CH₂— diphenylmethyl 1633—CH₂CH₂ bond —O— 2-F-phenyl CH₂— 1634 —CH₂CH₂ bond —O— 3-F-phenyl CH₂—1635 —CH₂CH₂ bond —O— 4-F-phenyl CH₂— 1636 —CH₂CH₂ bond —O— 2-Cl-phenylCH₂— 1637 —CH₂CH₂ bond —O— 3-Cl-phenyl CH₂— 1638 —CH₂CH₂ bond —O—4-Cl-phenyl CH₂— 1639 —CH₂CH₂ bond —O— 2-Me-phenyl CH₂— 1640 —CH₂CH₂bond —O— 3-Me-phenyl CH₂— 1641 —CH₂CH₂ bond —O— 4-Me-phenyl CH₂— 1642—CH₂CH₂ bond —O— 2-MeO-phenyl CH₂— 1643 —CH₂CH₂ bond —O— 3-MeO-phenylCH₂— 1644 —CH₂CH₂ bond —O— 4-MeO-phenyl CH₂— 1645 —CH₂CH₂ bond —O—2-MeS-phenyl CH₂— 1646 —CH₂CH₂ bond —O— 3-MeS-phenyl CH₂— 1647 —CH₂CH₂bond —O— 4-MeS-phenyl CH₂— 1648 —CH₂CH₂ bond —O— 2-F₃C-phenyl CH₂— 1649—CH₂CH₂ bond —O— 3-F₃C-phenyl CH₂— 1650 —CH₂CH₂ bond —O— 4-F₃C-phenylCH₂— 1651 —CH₂CH₂ bond —O— 2,3-diF-phenyl CH₂— 1652 —CH₂CH₂ bond —O—2,4-diF-phenyl CH₂— 1653 —CH₂CH₂ bond —O— 2,5-diF-phenyl CH₂— 1654—CH₂CH₂ bond —O— 2,6-diF-phenyl CH₂— 1655 —CH₂CH₂ bond —O—3,4-diF-phenyl CH₂— 1656 —CH₂CH₂ bond —O— 3,5-diF-phenyl CH₂— 1657—CH₂CH₂ bond —O— 2,3-diCl-phenyl CH₂— 1658 —CH₂CH₂ bond —O—2,4-diCl-phenyl CH₂— 1659 —CH₂CH₂ bond —O— 2,5-diCl-phenyl CH₂— 1660—CH₂CH₂ bond —O— 2,6-diCl-phenyl CH₂— 1661 —CH₂CH₂ bond —O—3,4-diCl-phenyl CH₂— 1662 —CH₂CH₂ bond —O— 3,5-diCl-phenyl CH₂— 1663—CH₂CH₂ bond —O— 2-Cl-3-F-phenyl CH₂— 1664 —CH₂CH₂ bond —O—2-Cl-4-F-phenyl CH₂— 1665 —CH₂CH₂ bond —O— 2-Cl-5-F-phenyl CH₂— 1666—CH₂CH₂ bond —O— 3-Cl-4-F-phenyl CH₂— 1667 —CH₂CH₂ bond —O—3-Cl-5-F-phenyl CH₂— 1668 —CH₂CH₂ bond —O— 4-Cl-2-F-phenyl CH₂— 1669—CH₂CH₂ bond —O— 4-Cl-3-F-phenyl CH₂— 1670 —CH₂CH₂ bond —O—2,3-diMeO-phenyl CH₂— 1671 —CH₂CH₂ bond —O— 2,4-diMeO-phenyl CH₂— 1672—CH₂CH₂ bond —O— 2,5-diMeO-phenyl CH₂— 1673 —CH₂CH₂ bond —O—2,6-diMeO-phenyl CH₂— 1674 —CH₂CH₂ bond —O— 3,4-diMeO-phenyl CH₂— 1675—CH₂CH₂ bond —O— 3,5-diMeO-phenyl CH₂— 1676 —CH₂CH₂ bond —O— cyclopropylCH₂— 1677 —CH₂CH₂ bond —O— cyclobutyl CH₂— 1678 —CH₂CH₂ bond —O—cyclopentyl CH₂— 1679 —CH₂CH₂ bond —O— cyclohexyl CH₂— 1680 —CH₂CH₂ bond—O— 2-furanyl CH₂— 1681 —CH₂CH₂ bond —O— 2-thienyl CH₂— 1682 —CH₂CH₂bond —O— 2-pyridyl CH₂— 1683 —CH₂CH₂ bond —O— 3-pyridyl CH₂— 1684—CH₂CH₂ bond —O— 4-pyridyl CH₂— 1685 —CH₂CH₂ bond —O— 3-Me-2-pyridylCH₂— 1686 —CH₂CH₂ bond —O— 4-Me-2-pyridyl CH₂— 1687 —CH₂CH₂ bond —O—2-benzothienyl CH₂— 1688 —CH₂CH₂ bond —O— 2-benzofuranyl CH₂— 1689—CH₂CH₂ bond —O— 2-naphthyl CH₂—

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: A is O or S; Qis —OR¹ or —NR¹R²; R¹, at each occurrence, is independently selectedfrom: H; C₁-C₆ alkyl substituted with 0-3 R^(1a); C₂-C₆ alkenylsubstituted with 0-3 R^(1a); C₃-C₁₀ carbocycle substituted with 0-3R^(1b); C₆-C₁₀ aryl substituted with 0-3 R^(1b); and 5 to 10 memberedheterocycle substituted with 0-3 R^(1b); R^(1a), at each occurrance, isindependently selected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN,NO₂, NR¹⁵R¹⁶, CF₃; C₃-C₁₀ carbocycle substituted with 0-3 R^(1b); C₆-C₁₀aryl substituted with 0-3 R^(1b); and 5 to 6 membered heterocyclesubstituted with 0-3 R^(1b); R^(1b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R²independently selected from H, NH₂, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy,phenoxy, benzyloxy, C₃-C₁₀ carbocycle, C₆-C₁₀ aryl and 5 to 10 memberedheterocycle; R³ is —(CR⁷R^(7a))_(n)—R⁴,—(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(n)—S(═O)—(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(n)—S(═O)₂—(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(n)—C(═O)—(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(n)—N(R^(7b))C(═O)—(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(n)—C(═O)N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(n)—N(R^(7b))S(═O)₂—(CR⁷R^(7a))_(m)—R⁴, or—(CR⁷R^(7a))_(n)—S(═O)₂N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴; n is 0, 1, 2, or 3;m is 0, 1, 2, or 3; R^(3a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₂-C₄alkenyloxy; R⁴ is H, OH, OR^(14a), C₁-C₆ alkyl substituted with 0-3R^(4a), C₂-C₆ alkenyl substituted with 0-3 R^(4a), C₂-C₆ alkynylsubstituted with 0-3 R^(4a), C₃-C₁₀ carbocycle substituted with 0-3R^(4b), C₆-C₁₀ aryl substituted with 0-3 R^(4b), or 5 to 10 memberedheterocycle substituted with 0-3 R^(4b); R^(4a), at each occurrence, isindependently selected from is H, F, Cl, Br, I, CF₃, C₃-C₁₀ carbocyclesubstituted with 0-3 R^(4b), C₆-C₁₀ aryl substituted with 0-3 R^(4b), or5 to 10 membered heterocycle substituted with 0-3 R^(4b); R^(4b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ halothioalkoxy; R⁵is H, OR¹⁴; C₁-C₆ alkyl substituted with 0-3 R^(5b); C₁-C₆ alkoxysubstituted with 0-3 R^(5b); C₂-C₆ alkenyl substituted with 0-3 R^(5b);C₂-C₆ alkynyl substituted with 0-3 R^(5b); C₃-C₁₀ carbocycle substitutedwith 0-3 R^(5c); C₆-C₁₀ aryl substituted with 0-3 R^(5c); or 5 to 10membered heterocycle substituted with 0-3R^(5c); R^(5a) is H, OH, C₁-C₄alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄ alkenyloxy; R^(5b), at eachoccurrence, is independently selected from: H, C₁-C₆ alkyl, CF₃, OR¹⁴,Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶; C₃-C₁₀ carbocycle substituted with0-3 R^(5c); C₆-C₁₀ aryl substituted with 0-3 R^(5c); or 5 to 10 memberedheterocycle substituted with 0-3 R^(5c); R^(5c), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ halothioalkoxy; R⁶ is H; C₁-C₆alkyl substituted with 0-3 R^(6a); C₃-C₁₀ carbocycle substituted with0-3 R^(6b); or C₆-C₁₀ aryl substituted with 0-3R^(6b); R^(6a), at eachoccurrence, is independently selected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F,Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, phenyl or CF₃; R^(6b), at each occurrence,is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶,CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy;R⁷, at each occurrence, is independently selected from H, OH, Cl, F, Br,I, CN, NO₂, CF₃, and C₁-C₄ alkyl; R^(7a), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, aryl andC₁-C₄ alkyl; R^(7b) is independently selected from H and C₁-C₄ alkyl; Wis —(CR⁸R^(8a))_(p)—; p is 0, 1, 2, 3, or 4; R⁸ and R^(8a), at eachoccurrence, are independently selected from H, F, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl and C₃-C₈ cycloalkyl; X is a bond; C₆-C₁₀ arylsubstituted with 0-3 R^(Xb); C₃-C₁₀ carbocycle substituted with 0-3R^(Xb); or 5 to 10 membered heterocycle substituted with 0-2 R^(Xb);R^(Xb), at each occurrence, is independently selected from H, OH, Cl, F,Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄halothioalkoxy; Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; t is0, 1, 2, or 3; u is 0, 1, 2, or 3; R⁹ and R^(9a), at each occurrence,are independently selected from H, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; Vis a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,—C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—, —S(═O)₂NR^(19b)—,—NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or —OC (═O)—; Z is C₁-C₃alkyl substituted with 1-2 R¹²; C₆-C₁₀ aryl substituted with 0-4R^(12b); C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or 5 to 10membered heterocycle substituted with 0-3 R^(12b); R¹² is C₆-C₁₀ arylsubstituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substituted with 0-4R^(12b); or 5 to 10 membered heterocycle substituted with 0-3 R^(12b);R^(12b), at each occurrence, is independently selected from H, OH, Cl,F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄halothioalkoxy; B is

R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷;C₁-C₆ alkyl substituted with 0-2 R^(10a); C₆-C₁₀ aryl substituted with0-4 R^(10b); C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or 5 to 10membered heterocycle optionally substituted with 0-3 R^(10b); R^(10a),at each occurrence, is independently selected from H, C₁-C₆ alkyl, OR¹⁴,Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or aryl substituted with 0-4R^(10b); R^(10b), at each occurrence, is independently selected from H,OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ halothioalkoxy; R¹⁴, at eachoccurrence, is independently selected from H, phenyl, benzyl, C₁-C₆alkyl, or C₂-C₆ alkoxyalkyl; R^(14a) is H, phenyl, benzyl, or C₁-C₄alkyl; R¹⁵, at each occurrence, is independently selected from H, C₁-C₆alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆alkyl); R¹⁶, at each occurrence, is independently selected from H, OH,C₁-C₆ alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆alkyl); R¹⁷ is H, aryl, aryl-CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl;R¹⁸, at each occurrence, is independently selected from H, C₁-C₆ alkyl,benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆ alkyl); andR¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and—S(═O)₂—(C₁-C₆ alkyl); and R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,phenyl, benzyl or phenethyl.
 2. A compound of claim 1 wherein A is O; Qis —NR¹R²; R¹, at each occurrence, is independently selected from: H;C₁-C₆ alkyl substituted with 0-3 R^(1a); C₂-C₆ alkenyl substituted with0-3 R^(1a); R_(1a), at each occurrence, is independently selected fromH, OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃; C₃-C₆ cycloalkyl substituted with 0-3R^(1b); phenyl substituted with 0-3 R^(1b); and 5 to 6 memberedheterocycle substituted with 0-3 R^(1b); R^(1b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R² isindependently selected from H, NH₂, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy,phenoxy, and benzyloxy; R³ is —(CR⁷R^(7a))_(n)—R⁴,—(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(n)—S(═O)—(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(n)—S(═O)₂—(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(n)—C(═O)—(CR⁷R^(7a))_(m)—R⁴, —(CR⁷R^(7a))_(n)—NHC(═O)—(CR⁷R^(7a))_(m)—R⁴, —(CR⁷R^(7a))_(n)—C(═O)NH—(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(n)—NHS(═O)₂—(CR⁷R^(7a))_(m)—R⁴, or—(CR⁷R^(7a))_(n)—S(═O)₂NH—(CR⁷R^(7a))_(m)—R⁴; n is 0, 1, 2, or 3; m is0, 1, 2, or 3; R^(3a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₂-C₄alkenyloxy; R⁴ is H, OH, OR^(14a), C₁-C₆ alkyl substituted with 0-3R^(4a), C₂-C₆ alkenyl substituted with 0-3 R^(4a), C₂-C₆ alkynylsubstituted with 0-3 R^(4a), C₃-C₁₀ carbocycle substituted with 0-3R^(4b), C₆-C₁₀ aryl substituted with 0-3 R^(4b), or 5 to 10 memberedheterocycle substituted with 0-3 R^(4b); R^(4a), at each occurrence, isindependently selected from is H, F, Cl, Br, I, CF₃, C₃-C₁₀ carbocyclesubstituted with 0-3 R^(4b), C₆-C₁₀ aryl substituted with 0-3 R^(4b), or5 to 10 membered heterocycle substituted with 0-3 R^(4b); R^(4b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R⁵ is H, OR¹⁴; C₁-C₆alkyl substituted with 0-3 R^(5b); C₁-C₆ alkoxy substituted with 0-3R^(5b); C₂-C₆ alkenyl substituted with 0-3 R^(5b); C₂-C₆ alkynylsubstituted with 0-3 R^(5b); C₃-C₁₀ carbocycle substituted with 0-3R^(5c); C₆-C₁₀ aryl substituted with 0-3 R^(5c); or 5 to 10 memberedheterocycle substituted with 0-3R^(5c); R^(5a) is H, OH, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄ alkenyloxy; R^(5b), at eachoccurrence, is independently selected from: H, C₁-C₆ alkyl, CF₃, OR¹⁴,Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶; C₃-C₁₀ carbocycle substituted with0-3 R^(5c); C₆-C₁₀ aryl substituted with 0-3 R^(5c); or 5 to 10 memberedheterocycle substituted with 0-3 R^(5c); R^(5c), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, and C₁-C₄ haloalkoxy; R⁶ is H; C₁-C₆ alkyl substituted with0-3 R^(6a); C₃-C₆ carbocycle substituted with 0-3 R^(6b); or C₆-C₁₀ arylsubstituted with 0-3R^(6b); R^(6a), at each occurrence, is independentlyselected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶,phenyl or CF₃; R^(6b), at each occurrence, is independently selectedfrom H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R⁷, at each occurrence,is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, andC₁-C₄ alkyl; R^(7a), at each occurrence, is independently selected fromH, OH, Cl, F, Br, I, CN, NO₂, CF₃, aryl and C₁-C₄ alkyl; R^(7b) isindependently selected from H and C₁-C₄ alkyl; W is —(CR⁸R^(8a))_(p)—; pis 0, 1, 2, 3, or 4; R⁸ and R^(8a), at each occurrence, areindependently selected from H, F, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl and C₃-C₈ cycloalkyl; X is a bond; C₆-C₁₀ aryl substituted with0-3 R^(Xb); C₃-C₁₀ carbocycle substituted with 0-3 R^(Xb); or 5 to 10membered heterocycle substituted with 0-2 R^(Xb); R^(Xb), at eachoccurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂,NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; Y is a bond or—(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; t is 0, 1, 2, or 3; u is 0, 1, 2,or 3; R⁹ and R^(9a), at each occurrence, are independently selected fromH, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; V is a bond, —C(═O)—, —O—, —S—,—S(═O)—, —S(═O)₂—, —N(R¹⁹)—, —C(═O)NR^(19b)—, —NR^(19b)C(═O)—,—NR^(19b)S(═O)₂—, —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, —S(═O)NR^(19b)—,—C(═O)O—, or —OC (═O)—; Z is C₁-C₃ alkyl substituted with 1-2 R¹²;C₆-C₁₀ aryl substituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substitutedwith 0-4 R^(12b); or 5 to 10 membered heterocycle substituted with 0-3R^(12b); R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b); C₃-C₁₀carbocycle substituted with 0-4 R^(12b); or 5 to 10 membered heterocyclesubstituted with 0-3 R^(12b); R^(12b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, and C₁-C₄ haloalkoxy; B is

R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, S (═O) 2R¹⁷;C₁-C₆ alkyl substituted with 0-1 R^(10a); C₆-C₁₀ aryl substituted with0-4 R^(10b); C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or 5 to 10membered heterocycle optionally substituted with 0-3 R^(10b); R^(10a),at each occurrence, is independently selected from H, C₁-C₆ alkyl, OR¹⁴,Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-4R^(10b); R^(10b), at each occurrence, is independently selected from H,OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃;R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; R¹⁵, ateach occurrence, is independently selected from H, C₁-C₆ alkyl, benzyl,phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆ alkyl); R¹⁶, at eachoccurrence, is independently selected from H, OH, C₁-C₆ alkyl, benzyl,phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆ alkyl); R¹⁷ is H,aryl, (aryl)CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; R¹⁸, at eachoccurrence, is independently selected from H, C₁-C₆ alkyl, benzyl,phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆ alkyl); and R¹⁹, ateach occurrence, is independently selected from H, OH, C₁-C₆ alkyl,phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆alkyl); and R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzylor phenethyl.
 3. A compound of claim 2 of Formula (Ia)

or a pharmaceutically acceptable salt thereof, wherein: R³ is—(CR⁷R^(7a))_(n)—R⁴, —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or—(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴; n is 0, 1, or 2; m is 0,1, or 2; R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,propoxy, or butoxy; R⁴ is H, OH, OR^(14a), C₁-C₄ alkyl substituted with0-2 R^(4a), C₂-C₄ alkenyl substituted with 0-2 R^(4a), C₂-C₄ alkynylsubstituted with 0-2 R^(4a), C₃-C₆ cycloalkyl substituted with 0-3R^(4b), aryl substituted with 0-3 R^(4b), or 5 to 10 memberedheterocycle substituted with 0-3 R^(4b); R^(4a), at each occurrence, isindependently selected from is H, F, Cl, Br, I CF₃, C₃-C₁₀ carbocyclesubstituted with 0-3 R^(4b), aryl substituted with 0-3 R^(4b), or 5 to10 membered heterocycle substituted with 0-3 R^(4b); R^(4b), at eachoccurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂,NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; R⁵ is H, OR¹⁴; C₁-C₆alkyl substituted with 0-3 R^(5b); C₂-C₆ alkenyl substituted with 0-3R^(5b); C₂-C₆ alkynyl substituted with 0-3 R^(5b); C₃-C₁₀ carbocyclesubstituted with 0-3 R^(5c); aryl substituted with 0-3 R^(5c); or 5 to10 membered heterocycle substituted with 0-3R^(5c); R^(5a) is H, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄ alkenyloxy; R^(5b),at each occurrence, is independently selected from: H, C₁-C₆ alkyl, CF₃,OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶; C₃-C₁₀ carbocycle substitutedwith 0-3 R^(5c); aryl substituted with 0-3 R^(5c); or 5 to 10 memberedheterocycle substituted with 0-3 R^(5c); R^(5c), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, and C₁-C₄ haloalkoxy; R⁶ is H, methyl, or ethyl; R⁷, at eachoccurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂,CF₃, and C₁-C₄ alkyl; R^(7a), at each occurrence, is independentlyselected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, phenyl and C₁-C₄ alkyl;R^(7b) is independently selected from H, methyl, ethyl, propyl, andbutyl; W is —(CR⁸R^(8a))_(p)—; p is 0, 1, or 2; R⁸ and R^(8a), at eachoccurrence, are independently selected from H, F, C₁-C₃ alkyl, C₂-C₃alkenyl, C₂-C₃ alkynyl and C₃-C₆ cycloalkyl; X is a bond; C₆-C₁₀ arylsubstituted with 0-3 R^(Xb); C₃-C₁₀ carbocycle substituted with 0-2R^(Xb); or 5 to 10 membered heterocycle substituted with 0-2 R^(Xb);R^(Xb), at each occurrence, is independently selected from H, OH, Cl, F,Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; Y is a bondor —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; t is 0, 1, or 2; u is 0, 1, or2; R⁹ and R^(9a), at each occurrence, are independently selected from H,F, C₁-C₄ alkyl or C₃-C₆ cycloalkyl; V is a bond, —C(═O)—, —O—, —S—,—S(═O)—, —S(═O)₂—, —N(R¹⁹)—, —C(═O)NR^(19b)—, —NR^(19b)C(═O)—,—NR^(19b)S(═O)₂—, —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, or —S(═O)NR^(19b)—;Z is C₁-C₃ alkyl substituted with 1-2 R¹²; aryl substituted with 0-4R^(12b); C₃-C₁₀carbocycle substituted with 0-4 R^(12b); or 5 to 10membered heterocycle substituted with 0-3 R^(12b); R¹² is C₆-C₁₀ arylsubstituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substituted with 0-4R^(12b); or 5 to 10 membered heterocycle substituted with 0-3 R^(12b);R^(12b), at each occurrence, is independently selected from H, OH, Cl,F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; B is

R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷;C₁-C₆ alkyl substituted with 0-1 R^(10a); aryl substituted with 0-4R^(10b); C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or 5 to 10membered heterocycle optionally substituted with 0-3 R^(10b); R^(10a),at each occurrence, is independently selected from H, C₁-C₆ alkyl, OR¹⁴,Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-4R^(10b); R^(10b), at each occurrence, is independently selected from H,OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃;R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; R¹⁵, ateach occurrence, is independently selected from H, C₁-C₆ alkyl, benzyl,phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆ alkyl); R¹⁶, at eachoccurrence, is independently selected from H, OH, C₁-C₆ alkyl, benzyl,phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆ alkyl); R¹⁷ is H,aryl, (aryl)CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; R¹⁸, at eachoccurrence, is independently selected from H, C₁-C₆ alkyl, benzyl,phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆ alkyl); and R¹⁹, ateach occurrence, is independently selected from H, OH, C₁-C₆ alkyl,phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆alkyl); and.
 4. A compound of claim 3 wherein: R³ is—(CR⁷R^(7a))_(n)—R⁴, —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,—(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or—(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴; n is 0 or 1; m is 0 or 1;R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,or butoxy; R⁴ is H, OH, C₁-C₄ alkyl substituted with 0-2 R^(4a), C₂-C₄alkenyl substituted with 0-2 R^(4a), C₂-C₄ alkynyl substituted with 0-1R^(4a), C₃-C₆ cycloalkyl substituted with 0-3 R^(4b), aryl substitutedwith 0-3 R^(4b), or 5 to 10 membered heterocycle substituted with 0-3R^(4b); R^(4a), at each occurrence, is independently selected from is H,F, Cl, CF₃, C₃-C₆ cycloalkyl substituted with 0-3 R^(4b), phenylsubstituted with 0-3 R^(4b), or 5 to 6 membered heterocycle substitutedwith 0-3 R^(4b); R^(4b), at each occurrence, is independently selectedfrom H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂haloalkoxy; R⁵ is H, OR¹⁴; C₁-C₄ alkyl substituted with 0-3 R^(5b);C₂-C₄ alkenyl substituted with 0-2 R^(5b); or C₂-C₄ alkynyl substitutedwith 0-2 R^(5b); R^(5a) is H, OH, methyl, ethyl, propyl, butyl, methoxy,ethoxy, propoxy, butoxy, or allyl; R^(5b), at each occurrence, isindependently selected from: H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴,═O; C₃-C₆ cycloalkyl substituted with 0-2 R^(5c); phenyl substitutedwith 0-3 R^(5c); or 5 to 6 membered heterocycle substituted with 0-2R^(5c); R^(5c), at each occurrence, is independently selected from H,OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂haloalkoxy; R⁶ is H; R⁷, at each occurrence, is independently selectedfrom H, F, CF₃, methyl, and ethyl; R^(7a), at each occurrence, isindependently selected from H, F, CF₃, methyl, and ethyl; R^(7b) isindependently selected from H, methyl, and ethyl; W is a bond, —CH₂—,—CH(CH₃)—, —CH₂CH₂— or —CH(CH₃)CH₂—; X is a bond; phenyl substitutedwith 0-2 R^(Xb); C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or 5 to 6membered heterocycle substituted with 0-2 R^(Xb); R^(Xb), at eachoccurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂haloalkyl, and C₁-C₂ haloalkoxy; Y is a bond, —CH₂—V—, —V—, or —V—CH₂—;V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—, or—N(CH₂CH₃)—, Z is C₁-C₂ alkyl substituted with 1-2 R¹²; C₆-C₁₀ arylsubstituted with 0-4 R^(12b); C₃-C₆ carbocycle substituted with 0-3R^(12b); or 5 to 10 membered heterocycle substituted with 0-3 R^(12b);R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b); C₃-C₆ carbocyclesubstituted with 0-3 R^(12b); or 5 to 10 membered heterocyclesubstituted with 0-3 R^(12b); R^(12b), at each occurrence, isindependently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, andC₁-C₂ haloalkoxy; B is

R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷; C₁-C₄ alkyl substituted with 0-1 R^(10a);phenyl substituted with 0-4 R^(10b); C₃-C₆ carbocycle substituted with0-3 R^(10b); or 5 to 6 membered heterocycle optionally substituted with0-3 R^(10b); R^(10a), at each occurrence, is independently selected fromH, C₁-C₄ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenylsubstituted with 0-4 R^(10b); R^(10b), at each occurrence, isindependently selected from H, OH, C₁-C₄ alkyl, C₁-C₃ alkoxy, Cl, F, Br,I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; R¹⁴ is H, phenyl, benzyl, C₁-C₄ alkyl, orC₂-C₄ alkoxyalkyl; R¹⁵, at each occurrence, is independently selectedfrom H, C₁-C₄ alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and—S(═O)₂—(C₁-C₄ alkyl); R¹⁶, at each occurrence, is independentlyselected from H, OH, C₁-C₄ alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄alkyl) and —S(═O)₂—(C₁-C₄ alkyl); R¹⁷ is H, phenyl, 4-fluorophenyl,4-chlorophenyl, 4-methylphenyl, 4-trifluorophenyl,(4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-methylphenyl)methyl,(4-trifluorophenyl)methyl, methyl, ethyl, propyl, butyl, methoxymethyl,methyoxyethyl, ethoxymethyl, or ethoxyethyl; R¹⁸, at each occurrence, isindependently selected from H, methyl, ethyl, propyl, butyl, phenyl,benzyl, and phenethyl; and R¹⁹, at each occurrence, is independentlyselected from H, methyl, and ethyl.
 5. A compound of claim 4 of Formula(Ib) wherein:

or a pharmaceutically acceptable salt thereof, wherein: R³ is —CH₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂(CH₃)₂, —CH(CH₃)CH₂CH₃,—CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃,—CH═CH₂, —CH₂CH═CH₂, —CH₂C(CH₃)═CH₂, —CH₂CH═C(CH₃)₂, —CH₂CH₂CH═CH₂,—CH₂CH₂C(CH₃)═CH₂, —CH₂CH₂CH═C(CH₃)₂, cis-CH₂CH═CH(CH₃),cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃), trans-CH₂CH₂CH═CH(CH₃);—C≡CH, —CH₂C≡CH, —CH₂C≡C(CH₃), cyclopropyl-CH₂—, cyclobutyl-CH₂—,cyclopentyl-CH₂—, cyclohexyl-CH₂—, cyclopropyl-CH₂CH₂—,cyclobutyl-CH₂CH₂—, cyclopentyl-CH₂CH₂—, cyclohexyl-CH₂CH₂—,phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—,(2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂—,(2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—,(2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,(2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—,(2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,(3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl-4-F-phenyl)CH₂—,phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—,(4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—,(4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—,(2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—,(3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—,(2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—,(2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—,(3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—,(3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—, or R⁵ is —CH₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH₂(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃,—CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CH₂CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₂CH₃,—CH₂CH(CH₃)CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH(CH₂CH₃)₂, —CF₃, —CH₂CF₃,—CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂CH₂CF₃, —CH═CH₂, —CH₂CH═CH₂,—CH═CHCH₃, cis-CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃), trans-CH₂CH═CH(C₆H₅),—CH₂CH═C(CH₃)₂, cis-CH₂CH═CHCH₂CH₃, trans-CH₂CH═CHCH₂CH₃,cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH₂CH═CH(CH₃), trans-CH₂CH═CHCH₂(C₆H₅),—C≡CH, —CH₂C≡CH, —CH₂C≡C(CH₃), —CH₂C≡C(C₆H₅) —CH₂CH₂C≡CH,—CH₂CH₂C≡C(CH₃), —CH₂CH₂C≡C(C₆H₅) —CH₂CH₂CH₂C≡CH, —CH₂CH₂CH₂C═C(CH₃),—CH₂CH₂CH₂C≡C(C₆H₅) cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,cyclohexyl-CH₂—, (2-CH₃-cyclopropyl)CH₂—, (3-CH₃-cyclobutyl)CH₂—,cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—, cyclopentyl-CH₂CH₂—,cyclohexyl-CH₂CH₂—, (2-CH₃-cyclopropyl)CH₂CH₂—,(3-CH₃-cyclobutyl)CH₂CH₂—, phenyl-CH₂—, (2-F-phenyl)CH₂—,(3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, furanyl-CH₂—, thienyl-CH₂—,pyridyl-CH₂—, 1-imidazolyl-CH₂—, oxazolyl-CH₂—, isoxazolyl-CH₂—,phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—,(4-F-phenyl)CH₂CH₂—, furanyl-CH₂CH₂—, thienyl-CH₂CH₂—, pyridyl-CH₂CH₂—,1-imidazolyl-CH₂CH₂—, oxazolyl-CH₂CH₂—, isoxazolyl-CH₂CH₂—, W is a bond,—CH₂—, or —CH(CH₃)—; X is a bond;

Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; V is a bond, —C(═O)—, —O—, —S—,—S(═O)—, —S(═O)₂—, —NH—, or —N(CH₃)—, Z is phenyl 2-F-phenyl,3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl,2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl,3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl,2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl,3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl,3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl,2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF₃O-phenyl, 3-CF₃O-phenyl,4-CF₃O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl,4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,morpholino,N-piperinyl, phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—,(4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—,(4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—,(2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—,(3,5-diF-phenyl)CH₂—, (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—,(2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—,(3,5-diCl-phenyl)CH₂—, (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—,(3-Cl-4-F-phenyl)CH₂—, (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—,(4-MeO-phenyl)CH₂—, (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—,(4-Me-phenyl)CH₂—, (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—,4-MeS-phenyl)CH₂—, (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—,(4-CF₃O-phenyl)CH₂—, (furanyl)CH₂—, (thienyl)CH₂—, (pyridyl)CH₂—,(2-Me-pyridyl)CH₂—, (3-Me-pyridyl)CH₂—, (4-Me-pyridyl)CH₂—,(1-imidazolyl)CH₂—, (oxazolyl)CH₂—, (isoxazolyl)CH₂—,(1-benzimidazolyl)CH₂—, (cyclopropyl)CH₂—, (cyclobutyl)CH₂—,(cyclopentyl)CH₂—, (cyclohexyl)CH₂—, (morpholino)CH₂—,(N-pipridinyl)CH₂—, -phenyl-CH₂CH₂—, (phenyl)₂CHCH₂—,(2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—,(2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—,(2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—,(2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—,(3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—,(2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—,(2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—,(3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—,(3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—,(3-Cl-4-F-phenyl)CH₂CH₂—, (2-MeO-phenyl)CH₂CH₂—, (3-MeO-phenyl)CH₂CH₂—,(4-MeO-phenyl)CH₂CH₂—, (2-Me-phenyl)CH₂CH₂—, (3-Me-phenyl)CH₂CH₂—,(4-Me-phenyl)CH₂CH₂—, (2-MeS-phenyl)CH₂CH₂—, (3-MeS-phenyl)CH₂CH₂—,(4-MeS-phenyl)CH₂CH₂—, (2-CF₃O-phenyl)CH₂CH₂—, (3-CF₃O-phenyl)CH₂CH₂—,(4-CF₃O-phenyl)CH₂CH₂—, (furanyl)CH₂CH₂—, (thienyl)CH₂CH₂—,(pyridyl)CH₂CH₂—, (2-Me-pyridyl)CH₂CH₂—, (3-Me-pyridyl)CH₂CH₂—,(4-Me-pyridyl)CH₂CH₂—, (imidazolyl)CH₂CH₂—, (oxazolyl)CH₂CH₂—,(isoxazolyl)CH₂CH₂—, (benzimidazolyl)CH₂CH₂—, (cyclopropyl)CH₂CH₂—,(cyclobutyl)CH₂CH₂—, (cyclopentyl)CH₂CH₂—, (cyclohexyl)CH₂CH₂—,(morpholino)CH₂CH₂—, (N-pipridinyl)CH₂CH₂—, B is

R¹⁰ is H, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,(4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 4-Cl-phenyl, (4-Cl-phenyl)CH₂—,(4-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl, (4-CH₃-phenyl)CH₂—,(4-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl, (4-CF₃-phenyl)CH₂—, or(4-CF₃-phenyl)CH₂CH₂—.
 6. A compound of claim 4 wherein: B is


7. A compound of claim 4 of Formula (Id) wherein:

or a pharmaceutically acceptable salt thereof, wherein: R³ is R⁴, R⁴ isC₁-C₄ alkyl substituted with 0-2 R^(4a), C₂-C₄ alkenyl substituted with0-2 R^(4a), C₂-C₄ alkynyl substituted with 0-2 R^(4a), R^(4a), at eachoccurrence, is independently selected from is H, F, CF₃, C₃-C₆cycloalkyl substituted with 0-3 R^(4b), phenyl substituted with 0-3R^(4b), or 5 to 6 membered heterocycle substituted with 0-3 R^(4b);R^(4b), at each occurrence, is independently selected from H, OH, Cl, F,NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl,butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;R⁵ is C₁-C₄ alkyl substituted with 0-3 R^(5b); C₂-C₄ alkenyl substitutedwith 0-2 R^(5b); or C₂-C₄ alkynyl substituted with 0-2 R^(5b); R^(5b),at each occurrence, is independently selected from: H, methyl, ethyl,propyl, butyl, CF₃, OR¹⁴, ═O; C₃-C₆ cycloalkyl substituted with 0-2R^(5c); phenyl substituted with 0-3 R^(5c); or 5 to 6 memberedheterocycle substituted with 0-2 R^(5c); R^(5c), at each occurrence, isindependently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; W is —CH₂— or —CH(CH₃)—;X is a bond; phenyl substituted with 0-2 R^(Xb); C₃-C₆ cycloalkylsubstituted with 0-2 R^(Xb); or 5 to 6 membered heterocycle substitutedwith 0-2 R^(Xb); R^(Xb), at each occurrence, is independently selectedfrom H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl,and C₁-C₂ haloalkoxy; Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; V is abond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—, or—N(CH₂CH₃)—, Z is C₁-C₂ alkyl substituted with 1-2 R¹²; aryl substitutedwith 0-4 R^(12b); C₃-C₆ carbocycle substituted with 0-3 R^(12b); or 5 to10 membered heterocycle substituted with 0-3 R^(12b); R¹² is C₆-C₁₀ arylsubstituted with 0-4 R^(12b); C₃-C₆ carbocycle substituted with 0-3R^(12b); or 5 to 10 membered heterocycle substituted with 0-3 R^(12b);R^(12b), at each occurrence, is independently selected from H, OH, Cl,F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl,propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and C₁-C₂haloalkoxy; R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷; C₁-C₄ alkyl substituted with0-1 R^(10a); phenyl substituted with 0-4 R^(10b); C₃-C₆ carbocyclesubstituted with 0-3 R^(10b); or 5 to 6 membered heterocycle optionallysubstituted with 0-3 R^(10b); R^(10a), at each occurrence, isindependently selected from H, C₁-C₄ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN,NO₂, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-4 R^(10b); R^(10b), ateach occurrence, is independently selected from H, OH, methyl, ethyl,propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶,or CF₃; R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, butyl; R¹⁵, ateach occurrence, is independently selected from H, methyl, ethyl,propyl, and butyl; R¹⁶, at each occurrence, is independently selectedfrom H, OH, C₁-C₄ alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and—S(═O)₂—(C₁-C₄ alkyl); and R¹⁷ is H, phenyl, 4-fluorophenyl,4-chlorophenyl, 4-methylphenyl, 4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl) methyl, (4-methylphenyl)methyl,(4-trifluorophenyl)methyl, methyl, ethyl, propyl, butyl, methoxymethyl,methyoxyethyl, ethoxymethyl, or ethoxyethyl.
 8. A compound of claim 1 ofFormula (IIb) wherein:

or a pharmaceutically acceptable salt thereof, wherein: R³ is R⁴, n is 0or 1; m is 0 or 1; R⁴ is H, OH, C₁-C₄ alkyl substituted with 0-2 R^(4a),C₂-C₄ alkenyl substituted with 0-2 R^(4a), C₂-C₄ alkynyl substitutedwith 0-1 R^(4a), C₃-C₆ cycloalkyl substituted with 0-3 R^(4b), arylsubstituted with 0-3 R^(4b), or 5 to 10 membered heterocycle substitutedwith 0-3 R^(4b); R^(4a), at each occurrence, is independently selectedfrom is H, F, Cl, CF₃, C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),phenyl substituted with 0-3 R^(4b), or 5 to 6 membered heterocyclesubstituted with 0-3 R^(4b); R^(4b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂haloalkyl, and C₁-C₂ haloalkoxy; R⁵ is H, OR¹⁴; C₁-C₄ alkyl substitutedwith 0-3 R^(5b); C₂-C₄ alkenyl substituted with 0-2 R^(5b); or C₂-C₄alkynyl substituted with 0-2 R^(5b); R^(5b), at each occurrence, isindependently selected from: H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴,═O; C₃-C₆ cycloalkyl substituted with 0-2 R^(5c); phenyl substitutedwith 0-3 R^(5c); or 5 to 6 membered heterocycle substituted with 0-2R^(5c); R^(5c), at each occurrence, is independently selected from H,OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂haloalkoxy; W is a bond, —CH₂—, —CH(CH₃)—, —CH₂CH₂— or —CH(CH₃)CH₂—; Xis a bond; phenyl substituted with 0-2 R^(Xb); C₃-C₆ cycloalkylsubstituted with 0-2 R^(Xb); or 5 to 6 membered heterocycle substitutedwith 0-2 R^(Xb); R^(Xb), at each occurrence, is independently selectedfrom H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O—O)₂CH₃,C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; Y is abond, —CH₂—V—, —V—, or —V—CH₂—; V is a bond, —C(═O)—, —O—, —S—, —S(═O)—,—S(═O)₂—, —NH—, —N(CH₃)—, or —N(CH₂CH₃)—, Z is C₁-C₂ alkyl substitutedwith 1-2 R¹²; aryl substituted with 0-4 R^(12b); C₃-C₆ carbocyclesubstituted with 0-3 R^(12b); or 5 to 10 membered heterocyclesubstituted with 0-3 R^(12b); R¹² is aryl substituted with 0-4 R^(12b);C₃-C₆ carbocycle substituted with 0-3 R^(12b); or 5 to 10 memberedheterocycle substituted with 0-3 R^(12b); R^(12b), at each occurrence,is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, andC₁-C₂ haloalkoxy; B is

R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷; C₁-C₄ alkyl substituted with 0-1 R^(10a);phenyl substituted with 0-4 R^(10b); C₃-C₆ carbocycle substituted with0-3 R^(10b); or 5 to 6 membered heterocycle optionally substituted with0-3 R^(10b); R^(10a), at each occurrence, is independently selected fromH, C₁-C₄ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenylsubstituted with 0-4 R^(10b); R^(10b), at each occurrence, isindependently selected from H, OH, C₁-C₄ alkyl, C₁-C₃ alkoxy, Cl, F, Br,I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; R¹⁴ is H, phenyl, benzyl, C₁-C₄ alkyl, orC₂-C₄ alkoxyalkyl; R¹⁵, at each occurrence, is independently selectedfrom H, C₁-C₄ alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and—S(═O)₂—(C₁-C₄ alkyl); R¹⁶, at each occurrence, is independentlyselected from H, OH, C₁-C₄ alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄alkyl) and —S(═O)₂—(C₁-C₄ alkyl); R¹⁷ is H, phenyl, 4-fluorophenyl,4-chlorophenyl, 4-methylphenyl, 4-trifluorophenyl,(4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-methylphenyl)methyl,(4-trifluorophenyl)methyl, methyl, ethyl, propyl, butyl, methoxymethyl,methyoxyethyl, ethoxymethyl, or ethoxyethyl; R¹⁸, at each occurrence, isindependently selected from H, methyl, ethyl, propyl, butyl, phenyl,benzyl, and phenethyl; and R¹⁹, at each occurrence, is independentlyselected from H, methyl, and ethyl.
 9. A compound of claim 8 wherein: Bis


10. A compound according to claim 1 selected from: (2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;(2R,3S)N₁-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;and (2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(phenthyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;(2R,3S)N1-[1,3-dihydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;and (2R,3S)N1-[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.11. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 12. A pharmaceutical compositioncomprising a compound of claim 2 and a pharmaceutically acceptablecarrier.
 13. A pharmaceutical composition comprising compound of claim 3and a pharmaceutically acceptable carrier.
 14. A pharmaceuticalcomposition comprising a compound of claim 4 and a pharmaceuticallyacceptable carrier.
 15. A pharmaceutical composition comprising acompound of claim 5 and a pharmaceutically acceptable carrier.
 16. Apharmaceutical composition comprising a compound of claim 6 and apharmaceutically acceptable carrier.
 17. A pharmaceutical compositioncomprising a compound of claim 7 and a pharmaceutically acceptablecarrier.
 18. A pharmaceutical composition comprising a compound of claim1 and a pharmaceutically acceptable, carrier.
 19. A pharmaceuticalcomposition comprising a compound of claim 8 and a pharmaceuticallyacceptable carrier.
 20. A pharmaceutical composition comprising acompound of claim 9 and a pharmaceutically acceptable carrier.
 21. Apharmaceutical composition comprising compound of claim 10 and apharmaceutically acceptable carrier.
 22. A method for the treatment ofAlzheimer's Disease comprising administering to a host in need of suchtreatment a therapeutically effective amount of a compound of claim 1.23. A method for the treatment of Alzheimer's Disease comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of a compound of claim
 7. 24. A method for thetreatment of Alzheimer's Disease comprising administering to a host inneed of such treatment a therapeutically effective amount of a compoundof claim
 2. 25. A method for the treatment of Alzheimer's Diseasecomprising administering to a host in need of such treatment atherapeutically effective amount of a compound of claim
 3. 26. A methodfor the treatment of Alzheimer's Disease comprising administering to ahost in need of such treatment a therapeutically effective amount of acompound of claim
 4. 27. A method for the treatment of Alzheimer'sDisease comprising administering to a host in need of such treatment atherapeutically effective amount of a compound of claim
 5. 28. A methodfor the treatment of Alzheimer's Disease comprising administering to ahost in need of such treatment a therapeutically effective amount of acompound of claim
 6. 29. A method for the treatment of Alzheimer'sDisease comprising administering to a host in need of such treatment atherapeutically effective amount of a compound of claim
 8. 30. A methodfor the treatment of Alzheimer's Disease comprising administering to ahost in need of such treatment a therapeutically effective amount of acompound of claim
 9. 31. A method for the treatment of Alzheimer'sDisease comprising administering to a host in need of such treatment atherapeutically effective amount of a compound of claim 10.